The Therapeutic Role of Turmeric in Treatment and ...

Southeastern UniversityFireScholars

Selected Honors Theses

4-2015

The Therapeutic Role of Turmeric in Treatmentand Prevention of Alzheimer’s DiseaseRylan M. McQuadeSoutheastern University - Lakeland

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The Therapeutic Role of Turmeric in Treatment

and Prevention of Alzheimer’s Disease Rylan M. McQuade

Department of Natural Sciences. Southeastern University, Lakeland, Florida, USA

McQuade 2

Abstract: As a devastating neurological condition that expends millions of lives each

year, Alzheimer’s disease (AD) is a subject of intense investigation.1 Although AD has

been known for over a century, the precise mechanisms that underlie AD pathogenesis

and development are still poorly understood. The Alzheimer phenotype is typified by

extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs),

causing researchers to notice several key enzymes implicated in this process.1 Most

notable are β and γ secretases (which drive Aβ plaque production) and phospholipase

A2 (which stimulates major cascade activation through the specific cleavage of fatty acyl

esters).2 Both acidic and neutral sphingomyelinases of the ceramide pathway are also

strongly linked to AD development and progression.3,4

As a specific type of esterase,

PLA2 specializes in phospholipid catabolism by specifically cleaving fatty acyl bonds at

the sn-2 position, producing a free fatty acid and lysophospholipids as products.3,5

This

stimulates the arachidonic acid (AA) cascade, while lipid cleavage by sphingomyelinase

upregulates the ceramide pathway.3 Cyclooxygenase (COX) and lipooxygenase (LOX)

are suspected to be key players in oxidative and neurological damage and are involved in

both these metabolic pathways.4,5

A further investigation of these molecular messengers

and their cellular environments is absolutely essential for therapeutic intervention and

effective medical treatments. Recently, the role of herbal medicines has been investigated

to produce possible leads for Alzheimer’s treatment. Turmeric contains over 20

medicinally useful compounds, of which curcumin is a key component.6 In this review,

we hypothesize that turmeric will prove especially useful in preventing amyloid-β plaque

deposition in early stages of AD and improvement of learning and coordination in middle

stages of the disease. Further evidence suggests curcumin’s efficacy in resisting ROS,

preventing tau aggregation, and limiting the spread of pro-inflammatory molecules

throughout the body. Because of its highly beneficial effects as an Alzheimer therapeutic,

we commend that turmeric be studied in greater detail and incorporated into Western

medical treatments. Additionally, a prospective study will be presented to determine the

efficacy of turmeric therapies, both in improving physical activities and overall

neurological health. Although turmeric’s precise mechanisms are not yet understood,

multiple studies have confirmed its beneficial effects in preventing amyloidogenesis by

modulating esterase and sphingomyelinase activities and also resisting misdirected

McQuade 3

cleavage of APP.2 Turmeric has also been found to downregulate abnormal GSK-3β

function and prevent formation of SPs and NFTs. Interestingly, murine models subjected

to a turmeric regimen not only displayed a reversal of AD symptoms, but also

demonstrated a lower susceptibility to neurodegenerative disease.3 Collectively, these

findings strongly support turmeric’s therapeutic use in Western medicine.

Chapter 1

Introduction

As a widespread ailment that affects millions worldwide, AD wreaks a deadly

impact on the elderly population.4 Recently, the Western world has experienced a

dramatic peak in Alzheimer’s incidence.5 In this year alone (2015), over five million

Americans are currently living with AD. Certainly, Alzheimer’s is nothing new. Cases of

pre-senile dementia have been reported from early Mesopotamia and ancient Egypt when

external manifestations of the disease were noticed without much (if any) understanding

of its inner workings.6 Recently, however, AD has struck with a dogged intensity to

become one of the leading causes of death among Western cultures. What are the reasons

for AD’s sudden appearance? How does this disease begin and what are its hallmark

symptoms? Genomic comparisons and intensive genetic research reveal that humans have

always possessed the potential for AD development.6 Indeed, AD pathology seems to be

permanently etched on the Homo sapiens genome, consistently conserved from one

generation to the next. Because of the body’s intrinsic ability to produce β and γ

secretases, anyone can develop insoluble plaque deposition when secretases are

overstimulated. Similarly, every individual has the ability to develop NFTs from

excessive tau protein phosphorylation.7 With improved living conditions and medical

treatment, the geriatric population has increased substantially in recent years and

correlates closely with increasing AD incidence. AD largely affects the elderly, usually

65 years or older.5

Alzheimer’s disease progression is split into three overlapping categories: First, the

subject find is difficult to remember recent events. This period usually lasts around two to

McQuade 4

four years and is typified by mild bouts of confusion concerning daily routine and

activities.8 Next, the patient enters a stage of persistent confusion, often forgetting the

identities of close friends and family members. This part of disease progression is

especially devastating since it often robs the patient of his or her self-identity as neuronal

necrosis occurs more rapidly.9 Finally, the individual enters a sudden onset of physical

and cognitive decline, ultimately leading to death. Disease progression is a prolonged and

bitter defeat, stripping away memories and leaving feelings of social isolation and a lost

personal identity in their place. Countless therapies have been developed for AD, ranging

from COX-2 inhibitors to more progressive drugs like memantine and NSAIDs.10

Despite

displaying some promise, these drugs are largely inefficient in addressing the root cause

of AD pathology. The failure of modern AD therapies has driven researchers to delve

further, searching for the most effective treatment. Recent studies suggest that turmeric

may possess the clinical and pharmacological effects that reverse AD symptoms while

also preventing disease pathology. This chapter will review AD’s enormous impact on

the Western world, the rising cost of research, and the lipase enzymes involved in driving

amyloidogenesis. It will be shown precisely how enzymes like secretases and PLA2

directly impact AD development by producing Aβ peptides and pro-inflammatory

molecules respectively.

Alzheimer’s and the Western World

Due to the rising cost of neuropathological research and increasing incidence of

neurodegenerative diseases, much of current research is turning to homeopathic remedies,

largely derived from plant-based materials.3 The use of turmeric corresponds with many

aspects of Adurvedic (Indian) medicine and is frequently used in tandem with additional

Adurvedic compounds, such as Convolvulus pluricaulis (CP), liquiritin (obtained from

liquorice), and shankhpushpi (gathered from the alowe weed). Despite its frequent

medicinal use in much of Eastern medicine and its promising neurological benefits from

multiple studies, turmeric (to this date) is still not used therapeutically in Western

medicine. As researchers are desperately screening novel compounds and developing

McQuade 5

molecular analogues for the treatment of AD, turmeric (specifically curcumin) must be

examined more thoroughly as a potential candidate for AD medicines. Before turmeric

can be investigated in further detail, however, the basic mechanisms underlying AD must

be presented and understood.

As a fatal neurological disease that expends millions of lives each year, AD is a

major health concern among developed countries. It is especially prevalent across North

America and Europe, causing significant health concerns worldwide.11

In Western

cultures, individuals of 65 years exhibit an AD occurrence of 8%; this figure escalates

dramatically with age, affecting over 45% of 85-year-olds.4 With increasing medical

costs and rising expenditure of drug screening, many researchers are searching for

simpler, more efficient alternatives. Rather than halting disease conditions, current

treatments are merely palliative, hoping to ease symptoms in spite of internal tissue

necrosis. In this regard, even the most developed therapeutics are incompetent to prevent

AD pathogenesis and development.10

Researchers are desperately searching for a cure but

so far have been left without any conclusive results. It seems that the search for designing

an effective AD drug regimen has all but exhausted its efforts and research is turning to

components of Eastern medicine that exhibit curative potential. As a key medicinal

compound and major dietary component in Eastern cultures, turmeric may be useful in

preventing the pathogenesis of AD, as well as easing symptoms. After presenting relevant

studies and outlining current understandings of the disease, the efficacy of turmeric

(specifically curcumin) will be discussed and evaluated. First, a comprehensive overview

of AD—its hallmark symptoms, its molecular and genetic origins within the body, and

molecular inhibitors to stop AD progression—will all be presented and discussed in

greater detail. Finally, turmeric’s novel properties and its exceptional use as a dose-

dependent therapeutic will be presented and examined.

Basics of AD

A devastating and dehabilitating illness, AD is the subject of intense

investigation. This disease is becoming increasingly common with millions of cases each

McQuade 6

year and exorbitant costs expended in treating the disease.10

A chronically progressive

category of dementia, AD drastically impacts memory and spatial learning capabilities.12

Patients diagnosed with AD typically survive only three to nine years following AD

onset, manifesting both physical and social deterioration.1 Although the subject of

exhaustive research, the exact cause of AD still remains uncertain. Approximately 5% of

cases are suspected to be genomically linked and are subject to the influence of many

polygenomic sequences.13

Other cases are presumed to be environmental, either linked to

diet or lifestyle choices that are detrimental to overall homeostasis. Understandably, head

trauma can lead to neural disruption, but more obscure factors (such as high blood

pressure) can easily form a complex web of AD’s causative factors. Alzheimer’s complex

ontology coupled with its multiple phenotypic effects and interlinked signaling cascades

provides a difficult scenario for researchers.14

Each new finding underscores the

conviction that AD is a multifactorial illness, stimulated by a host of complex molecular

interactions. Discovered over a century ago by Alois Alzheimer— a Bavarian psychiatrist

and neuropathologist— the mysteries behind AD remain enigmatic.15

Originally

categorizing the disease as “pre-senile dementia,” it was later termed “Alzheimer’s

disease” by Dr. Emil Kraepelin. AD typically afflicts elderly patients (65 years or older),

although pre-senile dementia in younger patients is also a well-documented

phenomenon.9 As mentioned earlier these pre-senile cases are often linked to genetic

abnormalities or to head trauma early in life. Alzheimer’s disease progression is split into

seven distinct stages, ranging from pre-onset of disease symptoms to severe cognitive,

social, and cellular dysfunction.15

As the most common form of dementia, AD patients typically display signs of

forgetfulness and short-term memory (STM) impairment.16

Over the years, symptoms

progressively worsen until the patient displays dramatic behavioral changes,

motor/kinetic imbalance, and gradual loss of coordinated movement. Left untreated, the

patient deteriorates and death inevitably follows within three to nine years.17

In nearly all

cases, AD onset is associated with internal neurofibrillary tangles (NFTs) and external

senile plaques (SPs).11

NFTs are mainly composed of excessively phosphorylated tau

protein, which is overexpressed and has become insoluble in the intracellular

McQuade 7

environment.18

This is most likely due to erroneous expression of the tau gene, causing

protein overexpression and misfolding. Alteration of protein configuration mainly occurs

when defects occurring in the protein’s 3-dimensional structure are not corrected by

molecular chaperones. Because of this buildup of misfolded proteins, synapse

degradation is a common phenomenon of most tauopathies.19

As neural junctions become

clogged and the axon and cell body become crowded with proteinaceous debris, neural

tissues deteriorate and the overall health of the patient decreases. Under normal

conditions, tau proteins help support microtubules and facilitate molecular transport

across the axon. In AD pathology, tau aggregates to form large secondary structures

called paired helical filaments that become tangled and interwoven, causing impairment

of neuronal functions.20

Contrastingly, SPs are mainly present extracellularly and consist almost entirely

of amyloid-β (Aβ) peptide. Ultimately, Aβ peptides originate from the APP gene, which

encodes the amyloid protein precursor (APP).21

Although APP is the substrate in a

myriad of enzymatic reactions, it is largely cleaved through the actions of three main

secretase enzymes-- α, β, and γ. In multiple studies, α-secretase has been noted for its

beneficial effects involving neural growth and protection.7 A disintegrin and

metalloprotease domain protein (ADAM), α-secretase is normally found near the cell

glycocalyx or imbedded as a transmembrane protein within the phospholipid bilayer.22

α-

secretase cuts APP (using ADAM10 and ADAM17) which creates the C-terminus (C83)

portion and the secretion of larger α APP, which collectively regulate brain function. The

C83 part is retained within the lipid bilayer where it is enzymatically cleaved by γ-

secretase, producing a P3 peptide.23

Although found mainly in the plasma membrane,

ADAM10 is also found in significant amounts in the Golgi apparatus. When a

transmembrane protein is cleaved so that its extracellular domain is freed, this is called

“ectodomain shedding.” In contrast to α-secretase, β- and γ-secretases are known to

stimulate the production of Aβ1-40 and Aβ1-42 oligopeptides, which are equally implicated

in AD development.24

In AD pathogenesis, β-secretase (BASE1) acts upon APP first,

cleaving APP at its N-terminus by a catalytic aspartate residue in its active site. This

produces sAPPβ and a C-terminal fragment (CTFβ) called C99 is produced. sAPPβ is

McQuade 8

then cleaved by γ -secretase at the C-terminus to make multiple Aβ oligopeptides.25

Studies overwhelmingly demonstrate that Aβ1-40 and Aβ1-42 are most detrimental to neural

health and are key players in AD pathology. Although originally soluble, Aβ plaques

eventually aggregate to assume their insoluble form.26

This is due to steric considerations

involving surface area, as well as intramolecular interactions that make the aggregates

insoluble. Although soluble polymers have been the main subject of concern, recent

research suggests that soluble plaques may be equally (if not more) deadly than the

insoluble form.27

Although the precise details behind their neurotoxicity still remain a

mystery, researchers have found that soluble (s) Aβ peptides exert a lethal impact on

miRNA, exerting their efforts through N-methyl-D-aspartate (NMDA) receptors and

through reactive oxygen species (ROS).28

This finding highlights the need for total

prevention of Aβ peptide production, both soluble and insoluble forms.

A portion of γ-secretase (presenilin-1) is a central component for APP’s activity.

Researchers have found that even slight structural changes in presenilin-1’s structure are

linked with familial AD (which appears early in life).29

Since Aβ plaque detection is

often obscured by confounding factors, AD diagnosis is often difficult and SPs are

usually observed in deceased specimens. Several methods, however, exist for AD

detection in vivo. Positron emission tomography (PET) allows recording of abnormalities

in glucose metabolism, while MRIs can relay shrinkage of neural tissue that is noticeably

smaller than healthy brain tissue.30

Behavioral studies reveal that AD primarily affects

hippocampal functions involving memory storage and the entorhinal cortex (a processing

portion of the temporal lobe). Further investigations reveal that TNF-α may indirectly

encourage AD development.31

TNF-α converting enzyme (TACE) is a type of ADAM

whose activity liberates TNF-α into the extracellular environment. These proteins usually

contain large amounts of cysteine residues, which are implicated in joining of cells and

protein aggregation caused by disulfide bonding. In recent years, tumor necrosis factor

(TNF) α is a subject of interest for researchers. As a master-regulator of the immune

system, it is involved in critical reactions involving bodily defense systems,

carcinogenesis, inflammation, and regulated cell death.32

It is mainly secreted by

macrophages that have been alerted to exogenous threats to immunity. The immune

McQuade 9

system is well known for its rapid response to exogenous threats and external insults to

the body. An invading bacterium, a virus, or even an epidermal abrasion are common

stimulatory factors of the immune response.33

The immune system’s control of

endogenous systems, however, is only beginning to be understood. Indeed, science has

only touched the tip of the vast iceberg in its understanding of internal immune

modulation.34

An immune response mounted against internal bodily components was

first noted by Dr. William Coley in 1968 when he found that macrophages could mount a

response to carcinogenesis.35

This proved a notable discovery, opening a range of

unknown possibilities for the body’s defense system. For centuries, physicians had

understood the concept of bodily defense against external insults (albeit poorly). Finding

of modulatory defense mechanisms against internal threats radically altered medicine’s

approach to treating illness. In fact, Dr. Coley’s finding brought about a substantial

paradigm shift, turning investigative research to consider internal mechanisms that

stimulated pathogenesis. As Susan Sontag describes in her treatise “Illness as Metaphor,”

pinpointing an internal origin of disease drastically changed patient self-perception.

Rather than being viewed as a foreign entity, illness suddenly assumes an esoteric and

mystical indwelling as part of the host organism, so that fighting illness is a struggle

waged against one-self. Coley’s discovery was roughly concurrent with Nixon’s war on

cancer—a federally-legislated struggle against an internal pathology—and the innovative

campaigns of Mary Lasker in her own political struggle against cancer.36

These

generously funded campaigns, however, did not live up to their potential because their

magnified intensity was severely limited in scope. Since then, research has broadened its

viewpoint in most aspects, approaching cancer as a multifaceted disease or even many

diseases confined within a shared category. Today’s cancer research even works in

tandem with the human genome project to “map” out a cancer cell’s genome, and

research is currently investigating the precise layout of the basal cell carcinoma genome.6

These systematic, top-down approaches will offer a more comprehensive understanding

of disease while simultaneously noting unique “fingerprint” aspects of cancers that are

individually unique. Rather than a monogenic disease, cancer is a body in cellular

disarray where cells are nonresponsive to their normal signaling components or are

overly stimulated to excessive growth.37

In carcinogenesis, normal protective functions

McQuade 10

involving cell division have been damaged or downregulated through dynamic molecular

factors. Based on this approach, similar tactics are being adopted for understanding

neurodegenerative diseases. The seminal observation that internal disarray of molecular

messengers and signaling factors is responsible for cancer is a prime corollary for AD.

Although all AD patients demonstrate characteristic features of the disease state, many

unique factors also emerge. This key aspect underlies the failure behind current drug

regimens, which typically treat external symptoms rather than addressing the root

molecular cause.38

Phospholipase A2 & Lipid Metabolism

Of all biological molecules, lipids are adept as energy-rich storage molecules,

forming lipid bilayers and micelles of cells, and are involved in many biochemical

cascades within the body.39

In fact, lipids are the body’s main energy source and (mole

for mole) pack more energy than their polysaccharide counterparts.40

However, the role

of lipids as mere storage molecules is growing rapidly antiquated due to recent research.

Lipids are critically important to overall health and wellbeing and that lipid composition

alone (both in cell membranes and plasma free fatty acids) is vital for health. In fact,

researchers have found that free fatty acids (FFAs) and their metabolites can even act as

secondary messengers to impact countless molecular interactions.41

Pathways involving

the normal metabolism of fats include the AA cascade and the ceramide pathway

(sphingomyelinase cascade).27

Taken together, these biochemical pathways are essential

for normal homeostatic conditions and are critically important in producing a wide

variety of signaling molecules. Imbalances in these cascades, however, can be

detrimental and even fatal in some cases. These two major cascades (the AA cascade and

the ceramide pathway) display frequent abnormalities in Alzheimer’s disease and other

neurological conditions.42

The arachidonic acid (AA) cascade is a highly complex

molecular signaling pathway that mediates a wide variety of bodily functions, using

lipids as its primary stimulation. The ceramide (or sphingosine) pathway involves the use

of COX and LOX enzymes for lipid metabolism.10

Thus, a more thorough investigation

of these pathways and their involvement in neuropathogenesis is crucially important for

McQuade 11

medicinal and therapeutic value. In particular, PLA2 and its role in the AA cascade will

be described in greater detail.

Phospholipase A2 (PLA2) is a critically important enzyme for the regulation of

lipid types within the body.43

Occurring in virtually all organisms, PLA2 is a ubiquitous

enzyme that exists in six major types: Secreted (sPLA2), cytosolic (Ca2+

-dependent),

calcium-independent, platelet activating factor acetylhydrolase (Groups VII and VIII),

lysosomal PLA2, and adipose-specific PLA2 (AdPLA2).44

Members of the PLA2 family

are organized according to disulfide bonding trends and their order of discovery.43

With

greater refinement of crystallography techniques in the 1970s, researchers made further

inroads into the precise molecular structure of sPLA2. Utilizing X-ray crystallography,

researchers uncovered an uncommonly high amount of cysteine residues in PLA2 (over

10% of its total amino acids), all of which contribute in disulfide bonding.45

Collectively,

PLA2 enzymes play vitally important roles throughout the body. Through modulating

lipid composition of phospholipid bilayers, controlling protein expression, and making

critically vital molecules for the body, PLA2 is intimately involved in a variety of bodily

functions.46

Recent research investigating lipid-signaling cascades has highlighted that

tight regulation of PLA2 is essential for proper bodily functions.21

This is accomplished

through chemical modification (phosphorylation) by MAPK (mitogen-activated protein

kinase) at Serine-505.45,47,48

Likewise, the presence of high levels of calcium ions (acting

simultaneously with phosphorylation of chemical groups) is thought to activate PLA2’s

enzymatic activity.46,21

The overall three-dimensional structure of sPLA2 is shown in

Figure 1. PLA2’s modulatory activity in the AA cascade is especially important for

preventing neurodegeneration and the creation of pro-inflammatory eicosanoid

molecules. The overall molecular structure of sPLA2 is shown in Figure 1. Observe the

N-terminal (positioned near the lower right corner) and the HI, H2, and H3 α-helices

(shown as long red coils).43

The β-wing (strangely absent in some plant species) is

depicted by antiparallel yellow arrows. The calcium-binding loop (shown in green) is

essential in binding and catalyzing substrate.22

Notice that sPLA2 consists of only one

polypeptide. The C-terminus is located near the top left of the diagram. Seven disulfide

bonds are shown in tan, which lend stability to PLA2’s overall structure. The two helical

McQuade 12

short turns (SH4 and SH5) are depicted as tight red loops. Interestingly, most aspects of

PLA2’s secondary structure (α helices and beta sheets) are conserved from one species to

another. This molecular homology underscores the extreme structural and functional

importance of PLA2’s secondary and tertiary configurations.

Arachidonic acid (AA) is a polyunsaturated fatty acid (PUFA) exhibiting a long, 20-

carbon skeleton with four cis double bonds (shown below in Figure 2). It cannot be

synthesized de novo in humans so it must be obtained exogenously from meats, eggs, and

other animal products, or synthesized from its precursor, linoleic acid. Under normal

circumstances, the body produces α-linolenic acid. Although some conversion does occur

to DHA, it does not occur readily.49

Therefore DHA is categorized as an essential fatty

Figure 1: The three-dimensional structure of

sPLA2. Notice that the α helices (shown in red)

and the β sheets (shown in yellow) are vital to the

protein’s overall conformation. As shown, the

cysteine residues are vital to the protein’s function.

Each cysteine contains a thiol group, which is

adept at bonding with other molecules and/or

protonating in solution. Additionally, thiol groups

possess the ability to form disulfide bridges—a

special biological function.

acid that must be obtained through diet. Fish and certain plant materials like coconut and

olive oils supply n-3 PUFAs.

expression, inhibit inflammation and oxidation, a

dynamics.49

AA is a fatty acid acyl chain with four

common fatty acids in the brain, AA has been linked to spatial learning, image

recognition, memory, and critical thinking skills. A study conducted Birch

demonstrated that infants (18

brain development compared to controls.

especially apparent in this study, as infants taking AA supplementation exhibited higher

thinking abilities than other infants of the same age.

(DHA) was provided to supplement AA, learning capabilities were accelerated even more

dramatically.50

PLA2, Acetyl-

metabolism and processing of AA and DHA. AA can be produced by linoleic acid

(18:2n-6), but the chemical reaction proceeds slowly in the brain although somewhat

faster in the liver.51

These molecules are involved in a series of interrelated pathways all

linked to a wide variety of biochemical activity.

McQuade


3 PUFAs.50

Researchers believe that DHA can modulate gene

expression, inhibit inflammation and oxidation, and correctly modulate membrane

AA is a fatty acid acyl chain with four cis double bonds. As one of the most


recognition, memory, and critical thinking skills. A study conducted Birch et al.

demonstrated that infants (18-months) receiving doses of AA demonstrated more rapid

ain development compared to controls.50

AA’s role in cognitive development became


thinking abilities than other infants of the same age.50

When docosahexaneoic acid


-CoA, and COX-2 mediators are all involved in the


6), but the chemical reaction proceeds slowly in the brain although somewhat


linked to a wide variety of biochemical activity.

McQuade 13


Researchers believe that DHA can modulate gene

nd correctly modulate membrane

the most


et al.

months) receiving doses of AA demonstrated more rapid

AA’s role in cognitive development became


ic acid


2 mediators are all involved in the


6), but the chemical reaction proceeds slowly in the brain although somewhat


McQuade 14

Arachidonic acid cascade—Lipid Catabolism & Inflammatory

Eicosanoids

As described previously, AA can be obtained exogenously through diet or through

chemical modulation of linoleic acid (which is also an omega-6 fatty acid).51

This occurs

through desaturation (addition of double bonds) and subsequent elongation of linoleic

acid’s hydrocarbon chain. Once produced, esterification then occurs to incorporate AA

into a plasma membrane phospholipid. Along with other 20-carbon fats like EPA and

DGLA, AA can form the hydrophobic tail of the phospholipid molecule, which remains

buried in the lipophilic portion of the membrane.52

Recently, researchers have discovered

that AA cascade is closely involved in inflammatory activity. When pro-inflammatory

environmental factors (exogenous) or endogenous factors are present, phospholipase is

stimulated to cleave the bond joining AA with the phospholipid.49

This liberates AA,

leaving it free for oxygenation to occur. Frequently, oxygenation of FFA is carried out by

cyclooxygenase (COX) molecules, which cleave two of FA’s alkene groups to add

oxygen atoms and increase overall saturation of the molecule. Collectively, these changes

produce a wide class of pro-inflammatory molecules called eicosanoids, which are used

as secondary messengers that signal inflammation and swelling within the body.53

As

Figure 3 depicts, COX enzymes produce thromboxanes (TX), prostaglandins (PGs), and

prostacyclins (PGIs). Since two of AA’s four double bonds have been cleaved,

eicosanoids produced in this way contain two double bonds and are classified as “series-

2” molecules.53

Notice that promiscuous enzymes called synthases are used in the

creation of new compounds. Cytochrome P450 is a heme-containing protein contained

within the mitochondrial inner membrane. It’s activity is crucial for the creation of

Figure 2: Arachidonic acid’s molecular structure.

As shown, AA has the ability in vivo to fold in on

itself, naturally decreasing its overall steric

hindrance and surface area. As a 20-carbon fatty

acid, AA is produced through carboxylation of the

16-carbon linoleic acid.

stimulatory hormones, cholesterol

bilirubin in the liver.54

leukotrienes (LTs).25

LTs are intimately involved in the 5

which activates LTC4, LTD4, and LTE4 (all three are classes of LTs that use cysteine

residues’ thiol groups for their enzymatic activity).

LTCs’ involvement in weakeni

murine models, neurons were systematicall

concentration). This was found to stimulate

dependent manner (shown below in

Figure 3: Production of pro

molecules from lipid cleavage by PLA

epoxides are created through the enzymatic

activity of CytP450 on AA. COX enzymes produce

PGs and TXs, which are present in various forms.

McQuade

stimulatory hormones, cholesterol and vitamin D production, and modification of

Lipooxogenase (LOX),

on the other hand, does not

tamper with the alkene bonds

and merely oxygenates the FA

molecule, ultimately producing

LTs are intimately involved in the 5-lipooxygenase (5LO) pathway,

LTC4, LTD4, and LTE4 (all three are classes of LTs that use cysteine

for their enzymatic activity).55

Further studies have confirmed

LTCs’ involvement in weakening of memory and learning abilities.56

In one study using

models, neurons were systematically exposed to Abeta1-42 oligopeptides (10

concentration). This was found to stimulate cysteinyl LTR expression in a concentration

below in Figure 4).

Production of pro-inflammatory

molecules from lipid cleavage by PLA2. As shown,

epoxides are created through the enzymatic

on AA. COX enzymes produce

PGs and TXs, which are present in various forms.

McQuade 15

modification of

Lipooxogenase (LOX),

on the other hand, does not

tamper with the alkene bonds

merely oxygenates the FA

molecule, ultimately producing

lipooxygenase (5LO) pathway,

LTC4, LTD4, and LTE4 (all three are classes of LTs that use cysteine

Further studies have confirmed

In one study using

oligopeptides (10 µM

concentration-

normal conditions, AA can exert negative genomic control on its own production.

When control of molecular messengers runs amok, however, AA often demonstrates

positive control to drive production of LTs and upregulate LOX and COX enzymes.

Discussion

Collectively, these data suggest that methods of modulating the AA cascade

essential for AD therapies.52,57

important part of lipid metabolism that must occur for regular homeostasis.

lipase activity is not only involved in controlling membrane lipid composition, but also

modulating inflammatory factors involved in the immune response. TXs

isolated from thrombocytes) and LTs (initially found in white blood cells) are key

components of the immunity and cell

Figure 4: LTRs stimulate amyloid

deposition. LTR signaling is frequently associated

with histamine and PG expression, which induce

further swelling and inflammation. LTRs, for

example, can stimulate smooth muscle of the

respiratory system, but excessive

is associated with asthma and allergic reactions.

McQuade

Besides chemical modulation

through its metabolites,

itself also exhibits

transcriptional control by

passing the nuclear membrane

and directly influencing

transcription factors.

rmal conditions, AA can exert negative genomic control on its own production.



Collectively, these data suggest that methods of modulating the AA cascade

57 PLA2-mediated cleavage of membrane phospholipids

important part of lipid metabolism that must occur for regular homeostasis. It appears that


modulating inflammatory factors involved in the immune response. TXs (originally


components of the immunity and cell-cell signaling.55

This finding suggests that AD

LTRs stimulate amyloid-beta plaque

deposition. LTR signaling is frequently associated

with histamine and PG expression, which induce

further swelling and inflammation. LTRs, for

example, can stimulate smooth muscle of the

respiratory system, but excessive LTR production

is associated with asthma and allergic reactions.

McQuade 16

Besides chemical modulation

through its metabolites, AA

also exhibits

transcriptional control by

passing the nuclear membrane

and directly influencing

transcription factors. Under

rmal conditions, AA can exert negative genomic control on its own production.57



Collectively, these data suggest that methods of modulating the AA cascade are

mediated cleavage of membrane phospholipids is an

It appears that


(originally


This finding suggests that AD

McQuade 17

therapies must specifically modulate these signaling cascades by allowing a homeostatic

amount of lipase-mediated cleavage to occur.46

The precise amount of PLA2 needed is

difficult to determine since it varies between individuals and is largely contingent upon

diet.50

As evident from the data presented in this section, a total paradigm shift is needed

to bring about substantially persistent results for AD patients. Future therapies must delve

to the root cause of AD by addressing the origins and subsequent development of the

disease. Despite exhaustive research, a foolproof medication has not been developed.17 It

is clear that abnormal PLA2 cleavage is a pivotal event for AD development and that the

rate of cleavage is essential for determining the fine balance between normal health and

AD development. Despite all the collective knowledge about AD, researchers are still

uncertain about its precise cause. Its effects (SPs and NFTs) can be easily noticed, but the

precise factors driving this disease still remain a mystery. There is a temptation among

researchers to develop therapies that target specific portions of the disease phenotype.

This position is untenable, however, since AD is a multifactorial illness, causing a

plethora of unbalanced activities within the body. Thus, it becomes evident that a therapy

that strongly impacts pathogenesis at a very early stage of illness is paramount. Precisely

what this therapy entails will be discussed in later chapters.

Chapter 2

Introduction

In addition to the AA cascade, a number of other mechanisms contribute to AD

ontology. The major players in this disease include overregulated secondary messengers

(such as PGs, TXs, and LTs), a specific kinase called glycogen synthase kinase-3β (GSK-

3β), and iron atoms that assault neural tissue.58

All these molecular factors are implicated

in stimulating aberrant secretase activity, upregulating signaling cascades and

extracellular plaque deposition, and accommodating neural toxicity.59

Originally named

for its ability to regulate glycogen synthase (a key enzyme in gluconeogenesis), GSK-3β

is a kinase enzyme present as two different forms (α and β) that has been implicated in

countless bodily processes.60

Under normal circumstances, it controls energy distribution,

McQuade 18

glycogen formation, and establishing the overall body plan during fetal development.61

Interestingly, GSK-3β is also involved in neuronal differentiation and its dysfunction is

strongly linked to down syndrome (DS) and Parkinson’s disease (PD).2 Researchers

testing pre-neuronal cells in murine DS models and DS human embryos found that GSK-

3β function was increased due to lowered phosphorylation of the enzyme.2 By exhibiting

a third copy of the AICD portion of the APP gene, DS leads to significant problems with

enzyme expression.59

Administration of lithium, however, was found to increase

phosphorylation to normal levels. This finding may lend credence to the role of lithium

therapy in treating AD. This is discussed in greater detail in “Lithium: A Curative

Agent?” In this chapter, GSK-3β’s involvement in AD will be examined as well as the

varied roles of secondary messengers and the neurotoxic effects of iron in driving AD

progression. The role of lithium as a therapeutic will be evaluated and determined in

chapter 3.

Secondary Messengers, GSK-3β, and the Role of Iron

AA, PGs, and LTs are all secondary messengers that relay chemical signals

throughout the body. Dysfunctions involving AA have been linked to many pathologies

and chemical reactions that involve PUFAs. Recent research suggests that PUFAs like

AA and DHA are deeply involved in membrane dynamics as well as influencing the

enzyme conformation and activity, regulating protein expression, and produce vitally

important products for use in the cellular environment. These fats are called “essential”

because they cannot be produced de novo, but rather must be obtained from an exogenous

source.53

Of all body organs, the brain has an exceptionally large amount of long-chain

PUFAs (LCPUFAs). Collectively, AA and DHA occupy over 90% of fats in the brain,

occupying over half of its non-aqueous mass.62

In the initial stages of this cascade, PLA2

is activated to cut phospholipids in the sn-2 position, liberating AA. PLA2 is upregulated

when G-protein coupled receptors (GPCRs) are occupied or when NMDA receptors are

activated by glutamate to allow for entry of calcium.28

In a widely used, generic form of

signal transduction, G-proteins activate adenylyl cyclase (AC), which drives cAMP to

interact with protein kinase A (PKA). Once activated, PKA is able to phosphorylate

McQuade 19

nearby enzymes to upregulate their activity.63

Once released, AA can either be

reincorporated back into plasma membranes or can undergo further reactions to form a

wide class of eicosanoid molecules. These include prostaglandins and thromboxanes (via

COX-2); epoxides (via cytochrome P450); leukotrienes (via lipoxygenases); or

hydroperoxy acids (via autooxidation).57

Although the precise method of conversion is

poorly understood, researchers found that AA can also be converted to anandamide.64

Collectively, the production of LTs and COX lead to underexpression of DHA, which is

important for brain vitality. In fact, multiple studies suggest that DHA may prevent

oxidation.65

Although several trials have shown that supplemental DHA seemed to

encourage oxidation in vitro instead of impeding it, most other research shows DHA’s

positive effect in counteracting inflammation.62

DHA may encourage oxidation in some

organisms due to its high levels of unsaturation, but in humans most studies have shown

beneficial results.66

Since DHA is useful in treating asthma, researchers speculate that it

might favorably impact the cPLA2 cascade and act to inhibit inflammation. Several in

vitro studies revealed that AA is still produced even in the presence of DHA, suggesting

that it is not effective in halting the cPLA2 signaling pathway. DHA and eicosapentaenoic

acid (EPA; n-3 C20:5) both stimulate production of docosatrienes and resolvins, which

both aid in neural function.1 Most notably, DHA is converted to neuroprotectin D1

(whose production can also occur via sAPPα).46

In addition to PKA, another kinase called GSK-3β exhibits regulatory activity

through excessive phosphorylation of presenilin-1.67

Researchers found abnormally

increased levels of this kinase within AD brains. Through its enzymatic control of

presenilin-1, it is closely linked to secretase cleavage of APP and the production of Aβ

oligopeptides.27

This enzyme plays a key role in the insulin signal transduction pathway

and AD symptoms develop when this system runs awry.68

In fact, recent research

suggests an increasingly close connection between type II diabetes and AD.69

A down-

regulated response to insulin is associated with biochemical changes in the

phosphatidylinositol-3 (PI3) kinase pathway. Neural tissue carries receptors for insulin

and these are regulated through the PI3 kinase pathway and by mitogen-activated protein

(MAP) kinase pathway.68

These pathways are highly dynamic and are chemically

regulated on a microsecond basis. Researchers found, for instance, that Akt/PKB

McQuade 20

activates the glucose transporter (GLUT) 4 to change its location on the neurolemma

plasma membranes.70(p4)

Akt/PKB also negatively impacts GSK-3 through the addition of

phosphate groups at the serine 9 position. Interestingly, insulin receptors (IRs) in neural

tissue are not only involved in meeting the brain’s need for sugar, but are also closely

involved with memory and understanding new concepts.68

The rate of APP cleavage and

tau phosphorylation is closely modulated by IRs. Collectively, these data indicate a closer

correlation between type II diabetes and AD than was previously assumed. Glucose

uptake by neuronal cells is critically important: on average, the brain consumes an

estimated 80% of ingested glucose.66

Finding efficient methods of controlling the MAP

and PI3 kinase signaling pathways is critically important in finding a cure for AD, since it

may also impact regulation of secretase activity. Results are currently conflicted

regarding concentrations of PI3 kinase: some AD brains demonstrate excessive PI3,

while others show a deficit of PI3 kinase.71

Disruption of these pathways causes

increased lactate production and lower ATP production because of disrupted glycolytic

pathways. In one significant study, steptozotocin (STZ) was administered in sufficient

amounts to cause onset of diabetes mellitus in murine test subjects.72

Interestingly, mice

administered STZ developed disruptions in short-term memory (STM) and several

behavioral/social alterations as well. These findings highlight the critical roles of insulin

and IRs for neural health, deepening a possible connection between diabetes and AD.41

These data show that IRs’ collective response to glucose impacts the nervous system

tremendously. Further research into neural IRs and their role in STM is essential for

discovering the connection between diabetes and AD.

Iron is another factor suspected in the ontology of AD.4 When APP is transcribed

to form mRNA, it can then be translated into an amino acid sequence. When iron is

present in large amounts in the brain, it over stimulates translation of the mRNA through

iron-responsive factors that are especially sensitive to iron stimulation.4 Therapeutics are

desperately needed to address the potentially harmful role of excess iron in CSF and

surrounding neural tissue. Multiple studies demonstrate that iron accumulation occurs

rapidly in neural tissue and can encourage Aβ plaque production. Iron and calcium levels

within the cell were increased when APP was overexpressed. The precise molecular

details behind this process still remain unknown. It is suspected, however, that metals

McQuade 21

already present in the extracellular environment are ingested and interact with APP.

Researchers also discovered lowered superoxide dismutase (SOD) concentrations in cells

with disregulated APP. This is probably due to the overexpression of metal-transporting

proteins. Contrary to expectations, transferrin was found to play a minimal role in this

process. Iron controls APP functions within the cell. It shares many features for how iron

response element (IRE) regulates the translation of ferritin L- and H mRNAs using its 5’

UTRs.

Sphingomyelinases, the Ceramide Pathway, & Soluble Aβ--

Pathogenesis of Inflammation

Ceramides are a class of fatty compounds made of sphingosine and a fatty acid.

Present in abundant amounts within the phospholipid bilayer, recent evidence has found

that ceramides are not merely building components of cells but also participate in a wide

variety of cellular activities.73

This activity ranges from differentiation, division, and

apoptosis. Ceramides (literally “waxy amides”) are created through several different

pathways, one of which is through enzymatic (SMase) breakdown of sphingomyelin.

Interestingly, ceramide production upregulates SOCS3, a gene that suppresses kinase

signaling. This leads directly to leptin and insulin insensitivity, further establishing the

diabetes-AD correlation.74

Low oxygen, reactive oxygen species (ROS), and UV

radiation are all factors that increase SMase activity, leading to the creation of ceramides.

When neural tissue is lacking sufficient oxygen, excessive ceramide production was

noticed in astrocytes of the hippocampus.68

This is most likely a response to swelling

caused by ischemic conditions.74

nSMases are mainly located in the phospholipid bilayer, while aSMases are found

in endosomal-lysosomal portions of the cell.75

Researchers hypothesize that nSMases

(especially nSMase2) are involved in AD pathogenesis. nSMase consists of a phosphate

group covalently bonded to a protein that contains five serine residues (S173, S208,

S289, S292, S299) that are remarkably consistent between species. In the presence of

certain stress stimuli, these residues can be phosphorylated to activate the protein.74

Tumor necrosis factor (TNF)- α, IL-1beta, and IL-6 are all secondary messengers

McQuade 22

implicated in stimulated ceramide production. The AA cascade joins the ceramide

pathway (which is highly activated in AD patients) through the interaction of these ILs.73

Researchers noticed major changes in sphingolipid pathways of patients displaying

neurodegenerative disorders.52

Plasma levels of these enzymes were determined by

increased levels of SMase and acid ceramidase, resulting in higher ceramide and

sphingosine concentrations.76

Both of these are secondary messengers are intimately

involved in cell maturation and death. Both ceramide and sphinogosine, for instance, can

activate caspases 3 and 9 that trigger apoptosis. It is thought that Aβ upregulates neutral

and acid SMases via cPLA2 and AA.77

Both kinds of SMases provide structural support

for BAC-1, which cuts the β-site of APP. Lowered amounts of SPs in Alzheimer’s

patients have been shown to prevent Aβ activity, producing a beneficial neurological

effect.8

Under normal conditions, AA regulates sphingomyelinase (SMase) function.75

In

AD pathology, however, Aβ peptides activate SMases (both acidic and neutral forms) to

induce neural apoptosis. Likewise, antioxidants inhibit SMase by blocking the activity of

cPLA2 or by targeting specific genes using antisense oligonucleotides.73

Sphingosine-1-

phosphate protects the brain by preventing stimulation of acidic sphingomyelinase. Many

researchers propose that AD begins with small modifications to the hippocampus as

insoluble plaques build up in the extracellular environment. This causes problems with

cell-cell signaling through synapses, ultimately causing neuronal death. This theory falls

short, however, when one realizes that hardly any correlation exists between dementia

and plaque formation. Also, recent research suggests that neuronal apoptosis is linked to

soluble concentrations of Aβ peptide oligomers, rather than the fibrous, insoluble kind.27

Using sections of mouse cerebrum, researchers determined that soluble Aβ oligomers are

toxic to the CA1 region of the hippocampus.68

Several additional studies created

transgenic murine models lacking plaque accumulation. Even in the absence of neural

plaques, these mice still developed neuropathies and learning problems.78

Collectively,

these studies lend credence to the theory known as the “soluble Aβ” hypothesis.79

Sphingolipids (ceramides) and their metabolic products are extremely important aspect of

this hypothesis. Ceramide is made through two major methods of production. It can either

be made through the breakdown of sphingomyelin by neutral sphingomyelinase (N-

McQuade 23

SMase) and acidic sphingomyelinase (A-SMase), which degrade sphingomyelin or

manufactured through ceramide synthase.73

This signal cascade is present in nearly all

cells, but ceramide is present in abnormally high concentrations in AD patients and

sphingomyelin amounts were low. This suggests that metabolism of sphingolipids and

production of cereamide leads to AD progression. Soluble Aβ leads to cell death because

of the cPLA2 pathway that makes AA. Also, excessive oxidation of fats, nucleic acids,

and proteins has been linked to damage caused by soluble and fibrous Aβ peptides.24, 26

In one significant study, immunoblot analysis and SDS-PAGE were used to

determine the histological location of Aβ peptides in vitro. After this, MAFP (methyl

arachidonyl fluorophosphate) was used to inhibit cPLA2. By stopping the activity of

cPLA2, AA liberation was prohibited. Through this study, the researchers found that

excessive production of AA is harmful to neurons of the cortex by stimulating SMase

activity. By using an MTT assay, the study found an inverse relationship between

arachidonic acid concentration and neuronal viability.13

Also, neurons exposed to AA

longer suffered more toxic effects. Neurons exposed to 5 µM of AA, for instance,

demonstrated an upregulation of N- and A-SMase activities even after only one hour of

incubation.80

Maximum SMase production occurred after 6 hours of exposure.

Desipramine and 3-O-methyl-sphingomyelin (3OMeSM) inhibit SMases and these

stopped apoptosis caused by AA. Results were also tested using different fatty acids

others than AA (stearic acid, oleic acid, and linoleic acid). Interestingly, the introduction

of these fatty acids did not lead to apoptosis or upregulation of SMase activity. These

results are supported by a similar study (Florent et al.) showing that docosahexaenoic and

eicosopentaenoic acids did not induce apoptotic activity in neurons.49

In fact, the results

suggested that these additional fatty acids were helpful for neuronal activity, while Aβ

oligomers may induce A- and N-SMase production. Antisense oligomers, Aβ (40-1),

were used as a control and did not induce SMase production. 3OMeSM and N-acetyl

cysteine (NAC) inhibit SMase and helped preserve neuronal integrity. Desipramine and

imipramine both inhibit A-SMase and also lead to lower rates of cell death. Strangely,

however, 3OMeSM and desipramine both encouraged cell death.73

This finding puzzled

researchers and still cannot be properly explained. Fumosin B1 inhibits ceramide

synthesis and inhibition of serine-palmitoyl transferase (a gateway enzyme for creating

McQuade 24

sphingolipids) caused no changes in rates of cell death. From this data, researchers

concluded that prevention of SMase activity greatly benefitted neuronal function by

lowering caspase-3 and caspase-9 activity (caused by soluble Aβ peptides).75

Amazingly,

1 µM concentrations of soluble Aβ peptides caused a 51% lowering of cell livelihood

after 24 hours of incubation. 3OMeSM and desipramine lowered soluble Aβ1-42-induced

apoptosis to 75 and 81%. Also, a study found that ceramide utilizes cathepsin-D (which is

manufactured by lysosomal A-SMase).27

When cathepsin-D was inhibited by an

octapeptide, this proved highly beneficial to neurons. Thus, overexpression of the

ceramide pathway (and associated overproduction of N- and A-SMases) are detrimental

to neural health and can stimulate development and progression of AD.

Genetics & Environmental Risk Factors

The risk of AD and cerebrovascular disease (CVD) is highly increased with the

possession of Apolipoprotein ε4 (APOE4) gene. Strokes are often a common side affect

with ApoE4 because CVD usually exhibits a phenotypic impact (like a cerebral

infarction) that cannot be noticed clinically. Unfortunately, many cerebral infarctions

remain unnoticed and can lead to strongly detrimental effects like stroke.81

Interestingly,

researchers have correlated white matter hyperintensities (WMH) to stroke incidence. For

individuals older than 65-years-old, AD is the fourth leading cause of morbidity. In the

initial stages, AD first affects thinking and memory and later muscle control.14

Hypertension, diabetes, smoking, high blood homocysteine, and previous strokes are all

thought to increase chances of AD onset.82

“Late-onset AD” is more common and more

closely corrlated to APOE4. “Early-onset AD” is correlated to a set of three genes. The

first codes for β-amyloid precursor protein (APP) of chromosome 21.42

The second codes

for presenilin-1 (PS1) on chromosome 14.77

The third codes for presenlin-2 (PS2) on

chromosome 1, which aids in presenilin degradation. These genes drive upregulation of

astrocytes and microglia, ultimately stimulating AD onset. Interestingly, demographic

studies have noticed AD’s infrequence in India and other parts of Asia. It is often debated

whether this is a result of diet or is genetically linked and/or cased by some other

McQuade 25

unnoticed factor. Genomic testing reveals that the ApoE4 gene is extremely low in India.

Because of their genetic variability, most Indian AD patients demonstrated differences in

disease progression, showing lower levels of oligometric Aβ1-42 peptides than their

American counterparts, as well as less heavily phosphorylated tau. These studies still

remain unclear and further testing is needed to determine the importance of these studies

for current Alzheimer research.

Impact of Neuroinflammation

Although tau aggregation and SP deposition are important in disease pathology,

neural inflammation seems to be the driving factor. This is hypothesized to occur through

excessive stimulation of AA and the production of pro-inflammatory eicosanoids

mentioned earlier. In one significant study, researchers used spontaneously hypertensive

rats (SHRs), which are characterized by hypertensivity, diabetic symptoms, and other

metabolic disorders. SHRs were chose because of their propensity to create eicosanoid

molecules, while Wistar-Kyoto (WKY) controls exhibited normal blood pressure and

produced fewer inflammatory factors. SHRs were found to demonstrate a more rapid

progression of AD, most likely due to widespread microglial activation. Microglial are a

special type of phagocytic cell within the nervous system that is stimulated to consume

threats to homeostasis. In the presence of inflammatory stimuli, microglia are alerted and

produce a variety of cytokines. Unfortunately, in the SHR rats this only lead to further

stimulation of tissue swelling. Under inflammatory stimuli, mitogen-activated protein

kinase (MAPK) is hyper-activated, leading to increased NFTs. This overall process is

shown below in Figure 5.

studies show that NFTs stimulate inflammation, while others suggest that pro

inflammatory cytokines precede disease onset.

demonstrated these results using tau transgenic (Tg) mice.

questions was whether inflammation or neural necrosis is the driving force behind AD.

Researchers found that abnormal tau expression may be caused by cytokine

Figure 5: Tau aggregation in AD neural tissue.

Abnormal tau expression leads to microglial

activation, which contribute to neuronal death.

Notice that the microglia clump together in

response to chemokine signals from neighboring

cells.

McQuade

Results are currently

conflicted regarding

inflammation’s role in

neurodegeneration. Some

studies show that NFTs stimulate inflammation, while others suggest that pro

inflammatory cytokines precede disease onset.12

A similar study (Yoshiyama

demonstrated these results using tau transgenic (Tg) mice.20

One of the researchers’ key


Researchers found that abnormal tau expression may be caused by cytokine

Tau aggregation in AD neural tissue.

Abnormal tau expression leads to microglial

activation, which contribute to neuronal death.

Notice that the microglia clump together in

response to chemokine signals from neighboring

McQuade 26

Results are currently

licted regarding

inflammation’s role in

neurodegeneration. Some

studies show that NFTs stimulate inflammation, while others suggest that pro-

A similar study (Yoshiyama et al.) also

One of the researchers’ key


McQuade 27

overproduction, a phenomenon that Zilka et al. have creatively called “cytokine storm.”19

When brain cells are damaged through ROS, for example, they can stimulate over-

activation of microglia, which upregulate their phagocytic activity to form large clusters

in the nervous system. This triggers an immune system response, which crowds blood

plasma with macrophages.83

Strangely, researchers found that immune system activation

can actually accelerate tau aggregation—ironically stimulating the very process it was

striving to prevent. By manipulating the fractalalkine-receptor for microglia (CX3CR1)

and the ligand for microglia (CX3CL1), researchers hoped to find a method of opposing

immune-stimulated neuroinflammation.19

Although extracellular levels of SPs decreased

in CX3CR1 knockout mice, intracellular tau protein concentrations increased.19

Hence,

Zilka et al’s study demonstrated mixed results: inhibition of the receptor lowered

insoluble plaques, but lead to an increase in NFTs. Although largely unsure why this

occurred, Zilka et al. concluded that their data supports the hypothesis of inflammation-

induced AD.19,74

This is certainly a matter of debate that cannot be conclusively decided;

however, the most current data suggests that neurodegeneration and the inflammatory

cascade can be largely attributed to the actions of the esterase PLA2 and its enzymatic

functions in the AA.45

Discussion

More than any other single finding, GSK-3β’s effect on neural insulin receptors

underscores the relationship between diabetes and AD. The precise molecular factors that

link these two illnesses must be researched in greater detail. How caloric (and sugar)

intake affects the metabolism of membrane lipids will be especially pertinent to this area

of study. Also, cholinergic receptors (typified by a positive response to acetylcholine) are

prime targets for future therapies. Finding methods of artificially stimulating these

receptors (especially through Galantine) may prove promising and must certainly be

studied in greater detail. Any potentially harmful effects of Galantine overstimulation

must be researched in greater detail. As a majorly activated cascade in AD, the ceramide

pathway must be targeted by a therapy that effectively addresses the disease. In

particular, SMases must be brought to normal plasma concentrations and ceramide

recruitment of caspase-3 and -9 must be inhibited. Also, although SPs and NFTs are a

McQuade 28

major issue, neuroinflammation seems to be a deeper problem. Research seems to

indicate that inflammatory signals are the motive driving force behind plaque deposition

and NFT accumulation.84

Therapies that specifically impede internal inflammation by

inhibiting enzyme overactivity (and the related “cytokine storm”) are sorely needed.

Also, patients who have suffered a stroke must be subjected to preemptive treatments to

halt pathogenesis and monitor the development of WHM. The immune-mediated

response of microglia is not intrinsically detrimental, but overactivated glia leads to

apoptotic activity.85

Following this theme, chapter 3 will present various current therapies

used to address AD symptoms. Finally, the therapeutic efficiency of turmeric will be

noted in comparison to other treatments.

Chapter 3

Introduction

Drawing from copious amounts of data, researchers are hoping to form a

constructive framework for an increased understanding of AD pathogenesis and

development. By direct chemical modulation of the AA and ceramide cascades (and

interception of the secondary messengers involved), researchers hope to design effective

drug regimens for AD patients. Thus far, the search for a cure has proven only

moderately successful. Due to the body’s complex molecular interchanges and formation

of intermediary structures, development of effective therapies with minimal side effects is

an extremely difficult endeavor.84

COX-2 inhibitors are a subject of special interest for

researchers, since modulation of these oxygenase molecules will prove vitally useful in

treating AD.86

However, as this chapter shows, even the most carefully concocted

therapies fall short of their desired intent. This failure is due mainly to ineffective

metabolism, misdirected tissue targeting, or through complications caused by adverse

effects. As discussed in this chapter, rofecoxib and celecoxib both exhibit therapeutic

promise, but are no longer widely used because of their potential fatality.87

This chapter

will examine many common pharmaceutical regimens used for AD patients, their

mechanism of action (if known), and their comparative success. Also, the cholinergic

McQuade 29

receptor hypothesis will be discussed relative to AD and a brief evaluation of how

different drug classes influence brain activity will be presented. Finally, the need to

incorporate turmeric into Western medicine will be presented and curcumin’s influence

on body systems will be examined in greater detail. Although not exhaustively

researched, turmeric’s medicinal benefits can be strongly inferred from numerous studies.

These studies indicate that turmeric offers a therapeutic remedy to replace ineffective

COX inhibitors, NSAID drugs, and other compounds like memantine.10,88

Searching for a Cure—Inhibitors and Molecular Intervention

Current medical treatments recognize the extreme importance of decreasing

inflammation, since it causes (or at the very least aggravates) neurodegeneration. Also,

treatments that address neurotoxins (such as rising iron concentrations and

overexpression of Aβ) are essential for treatment of AD. Current treatments seek to

address these issues using a variety of methods. First, there are molecular inhibitors that

specifically antagonize the activity of particular enzymes. COX-2 inhibitors are perhaps

the most widely known of this category. Cox-2 inhibitors (rofecoxib, celecoxib, and

others) have been used therapeutically, but exhibit less than desirable results (in some

cases even causing death). Likewise, glucocorticoids like prednisone have demonstrated

no observable improvements for memory, learning, and social interactions.89

COX-1 has

been shown to cause some inflammatory activity but it is also highly involved in

digestion, so its activity cannot be inhibited without causing gastrointestinal problems.19

Although NSAIDs were found to reduce swelling, they were inefficient at reducing Aβ

plaques.10

The inefficiency of most pharmaceutical drugs is due to a great deal of

educated guesswork and trial-and-error. In many ways, the drug design process itself is

experimental, based upon hypothesis and tweaking of the final drug product based upon

experimental results.90

Up to this point, these therapies have yielded highly discouraging

results. The most efficient therapy would effectively address swelling, reduction of

neuritic plaques, downregulation of tau protein, and normal regulation of PLA2. Once

these issues are addressed, AD can be effectively controlled. Also, an effective drug

McQuade 30

regimen for AD would address genomic regulation, which is often the source of enzyme

dysfunction.

Lithium—A Curative Agent?

Since the 1950s, lithium has been advanced as a neurological therapeutic for

mood and general neural homeostasis. Lithium has a long history of therapeutic use for

neurodegenerative diseases. Originally used to treat gout in the 1840’s, lithium has also

been clinically administered to bipolar patients for over 50 years.91

It has also been used

as an adjunct for blood pressure medication. The precise molecular mechanism of lithium

within the brain is poorly understood and it was prohibited after demonstrating negative

side effects, including the deaths of four patients.92

Many researchers hope it may prove

effective in treating neuropathies like AD. Lithium—originating from the Greek “Lithos”

(stone) since it was originally found in rocks-- was first discovered by Arfwedson, a

Swedish chemist, in 1817.93

Lithium exists as a positively-charged monovalent atom that

is interchangeable with other cations like potassium, sodium, and even divalent atoms

like magnesium and calcium.61 In the laboratory environment, lithium acts catalytically

on uric acid in the kidneys, although significant amounts are needed to induce these

results in vivo.94

By the 1880s, it was clinically prescribed for chronic depression and

other psychological abnormalities. By 1940, physicians realized a correlation between

sodium-rich diets and hypertension, and lithium was used to substitute sodium chloride as

a treatment for blood pressure.30

But in 1949, Corcoron et al. showed that lithium could

cause widespread tissue damage and even death, and its use as a therapeutic was

prohibited across America.95

This large-scale discrimination against lithium began to fade, however, when a

study conducted by Cade noted the sedentary effect of lithium on guinea pigs.91

Cade

theorized that mental problems were caused by a hitherto unrecognized poisonous agent,

which was then excreted in urine. In one notable study, Cade injected lithium urate into

guinea pigs, causing them to become sedated. Lithium chloride is the only dissolvable

salt in uric acid, which lead to sedation. This study reinvigorated the therapeutic use of

lithium carbonate in the treatment of neurological diseases. Interestingly, lithium

McQuade 31

carbonate showed no effect in schizophrenia or depression, but it was effective in all ten

manic patients in one study.93

After these hopeful results, lithium chloride became the

first FDA-approved drug for bipolar disorder.96

The practice of prescribing lithium may

have historical precedent. In the 5th century A.D., Caelius Aurelianus recommended

alkaline water for mentally disturbed patients, which may have contained high

concentrations of dissolved lithium ions.91

At this point, research remains inconclusive

and further studies must be done to determine the precise mechanisms of lithium’s

clinical efficacy. However, recent studies have uncovered the chemical interactions

involved in lithium’s usefulness as a therapeutic. Recently, lithium has been shown to

impact adenylyl cyclase (AC), which is an important cellular modulator for countless

chemical reactions.61

Both cyclic adenosine monophosphate (cAMP) and AC modulate

the effects of cAMP in the body for countless biological reactions. AC transforms ATP to

cAMP by way of a multistep process. Then cyclic nucleotide phosphoidiesterase changes

cAMP to AMP.95

This is a common event in signal transduction pathways, followed by

subsequent phosphorylation of specific protein targets. Protein kinase A (PKA) is

involved in this process through the removal of phosphate molecules.91

Lithium

upregulates cAMP and PKA activities by increasing enzyme binding efficiencies. Thus,

lithium serves as a metal catalyst that improves reaction conditions and accelerates the

reaction. Mori et al. found that lithium prohibits the transfer of phosphate groups by PKA

in microtubule sections of rat brains. This is accomplished when lithium vies with

magnesium at the C subunit of PKA.

Recent research suggests that lithium may play crucial roles in protecting neurons

and may be therapeutically valuable in treating AD, Parkinson’s, Huntington’s disease,

Amyotrophic lateral sclerosis, and ischemic conditions. Also, it can block N-methyl-D-

aspartate (NMDA) receptors and helps neuroregulatory proteins. As one of the first

proteins discovered that regulates apoptotic activity, B-cell lymphoma/leukemia-2 (Bcl-

2) gene can antagonize potential hazards like absence of growth factors, radiation,

glucocorticoid hormones, and oxidative agents like hydrogen peroxide.97

Bcl-2

upregulates caspase and increases mitochondrial calcium influx. Lithium causes higher

Bcl-2 levels in the cortex, hippocampus, and striatum and also lowers concentrations of

protein 53, which normally induces apoptosis.97

It also stimulates Akt, a class of protein

McQuade 32

kinases that specifically utilizes serine and threonine and is controlled by the

phosphatidylinositol kinase molecular cascade.97

GSK-3β prevents overproduction of β-

catenin by degrading it over time. Long-term administration of lithium increases β-

catenin in murine models. AD is frequently associated with misreadings in presenilin

protein, which leads to lower levels of β-catenin. This is linked to apoptosis by Aβ plaque

accumulation. Presenilin-1 joins with β-catenin, leading to a lower energy state. Low

levels of GSK-3α are directly correlated to Aβ concentrations, whereas GSK-3β produces

the inverse effect. Prevents Aβ being made from APP. A study by Feyt et al., however,

offers conflicting data to these studies involving lithium as a therapeutic agent for AD.97

Thus, although lithium should be considered a viable candidate in treating AD, much

more research is needed to prevent detrimental effects. Lithium may be incorporated as a

therapeutic, but only after plentiful research has been conducted to verify its beneficial

effects while preventing neurotoxicity.

New Frontiers-- Memantine & NSAIDS for AD Therapy

Cholinergic neurons are characterized by their responsiveness to acetylcholine

and upregulating cholinergic neuron activity is a prime target for therapies. Molecules

that antagonize cholinesterases are the most efficient type of inhibitor used because they

prevent the enzymatic deconstruction of cholinergic receptors.98

Through conservation of

these receptors, acetylcholine is encouraged to remain within the synaptic cleft and

participate in vital neural functions. Galantamine, Rivastigmine, Donepezil, and Tacrine

are four of the most commonly used compounds to prevent cholinesterase activity. Drugs

that exhibit this type of activity are currently the only officiated drug for AD.98

As AD

progresses, however, these treatments grow less potent, gradually losing their efficiency

over time. It is hypothesized that cholinesterases gradually lose their responsiveness to

treatments or find methods of avoiding the intended therapy. Thus, although

cholinesterase inhibitors are headed in the right direction, they are not a viable, long-term

solution. NMDA inhibitors are also a topic of interest. Memantine, in particular, is

especially effective through its prohibition of excessive AA release.88

The process of

synthetic memantine production is shown below in Figure 6. Although memantine may

prove promising, researchers are concerned that it may prove too constricting on AA

production.88

commonly used NSAID, is now prescribed for a variety of ailments. Now it is often taken

to preemptively stop the occurrence of strokes and myocardial infarctions.

commonly utilized drug in Western medicine, aspirin is useful for a variety of activities,

including reducing fever, pain, and inflammation. Multiple studies suggest that aspirin

taken in combination with DHA may prevent the pro

When placed in the same chemical environment as omega

production of resolvins, protectins, and oxoderivatives that collectively protect

neurological tissues.99

AD is often associated with vascular dementia (VaD), which is typified by abnormal,

undetectable growth of the brain’s capillaries.

often remains undiscovered clinically. In fact, VaD phenotype is so internalized that

autopsies are the most frequent method

display inflammation as a normal sign of aging; unchecked, however, inflammation can

quickly turn pathological over time. As plasma cytokine concentrations rise, astrocytes

Figure 6: The synthetic production of memantine. As a

therapeutic used in AD treatment, memantine is an incredibly

important compound.39,70 Once obtaining the starting reactant,

its three-step laboratory synthesis is relatively straightforward.

The final production of HCl (shown beside the memantine

product) is also medicinally useful in low doses.

McQuade


Nonsteroidal anti-inflammatory

drugs (NSAIDs) are compounds

meant to counteract AD

pathology. Aspirin, the most


to preemptively stop the occurrence of strokes and myocardial infarctions.19



nation with DHA may prevent the pro-inflammatory activity of AD.

en placed in the same chemical environment as omega-3 PUFAs, aspirin leads to the



wth of the brain’s capillaries.81

This occurs early on in the disease and

overed clinically. In fact, VaD phenotype is so internalized that

utopsies are the most frequent method of VaD detection.100

Elderly patients often

ation as a normal sign of aging; unchecked, however, inflammation can

turn pathological over time. As plasma cytokine concentrations rise, astrocytes

The synthetic production of memantine. As a

therapeutic used in AD treatment, memantine is an incredibly

Once obtaining the starting reactant,

step laboratory synthesis is relatively straightforward.

The final production of HCl (shown beside the memantine

product) is also medicinally useful in low doses.70

McQuade 33


inflammatory

SAIDs) are compounds

meant to counteract AD

Aspirin, the most


As the most



inflammatory activity of AD.99

3 PUFAs, aspirin leads to the



This occurs early on in the disease and

overed clinically. In fact, VaD phenotype is so internalized that

Elderly patients often

ation as a normal sign of aging; unchecked, however, inflammation can

turn pathological over time. As plasma cytokine concentrations rise, astrocytes

McQuade 34

swell in a phenomenon known as astrogliosis.74

Found in the central nervous system

(CNS), astrocytes are star-shaped cells that participate in a wide variety of reactions, such

as providing structural support and nourishment to neurons. They also constitute the

lining of the blood-brain barrier (BBB), exchange substances between neural parenchyma

and blood plasma, communicate through surface contact with other neurons, increase

synapse connections, and facilitate signal transduction from one neuron to another.75

Astrogliosis stimulates a vicious cycle where inflamed tissues release more pro-

inflammatory molecules, leading to deadly results.

Receptors in the brain are divided into two major categories: nicotinic and

muscarinic. Nicotinic receptors are typified by ligand-gated ion channels embedded in the

neurolemma and at the neuromuscular junction. Both receptor types are cholinergic,

meaning that they respond to acetylcholine to propagate a signal along the axon to a

neighboring neuron, or to directly stimulate muscle contraction.98

Although both are

responsive to ACh, they are differentiated by their response to other compounds. For

instance, nicotinic acetylcholine receptors (nAChRs) are characterized by their response

to nicotine, while muscarinic acetylcholine receptors (mAChRs) are stimulated by

muscarine-- a substance originally found in the poisonous mushroom Amanita

muscaria.98

mAChRs are G-protein coupled receptors (GPCRs), which is the starting

point for the types of signal transduction described earlier. nAChRs are severely depleted

in AD. As discussed previously, cholinesterase inhibitors (ChEIs) are frequently used

during early stages of the disease, but they do not provide optimal results and show

limited efficiency. Researchers suspect that poor response may be due to gene variability.

Single nucleotide repeats (SNRs) were noted in PRKCE and NBEA, which are both gene

regions associated with cholinergic receptor functionality.101

α-nAChR is mainly

conserved between individuals and plays key roles throughout the CNS, originating from

CHRNA7 (on chromosome 15q14).101

Researchers noted that genetic differences in this

gene can impede AD development, slowing down disease progression in some patients.

Interestingly, gender differences can contribute genetic variations for how these receptors

are encoded and expressed. More than likely, this is due to the influence of sex hormones

upon these receptors.101

Control of nAChR by Galantamine (a ChEI) is depicted below in

Figure 7.

Many studies noted the connection that many nonsteroidal drug

inflammation demonstrated lower AD incidence.

noticed that Aβ and tau protein concentrations decreased upon administration of these

nonsteroidal drugs. Although the underlying mechanism f

unknown, it is suspected that

Figure 7: Modulatory Control of Neural Receptors by

Galantamine. As noted in the figure, binding of Galantamine

to receptors stimulates nAChR receptors, improves

memory, and promotes overall neural health.

McQuade


Many studies noted the connection that many nonsteroidal drugs to prevent arthritic

demonstrated lower AD incidence.6 Likewise, multiple animal studies

and tau protein concentrations decreased upon administration of these

Although the underlying mechanism for these drugs’ efficiency is still

that γ-secretase is antagonized by these drugs. Inhibition of

Modulatory Control of Neural Receptors by

. As noted in the figure, binding of Galantamine

to receptors stimulates nAChR receptors, improves

memory, and promotes overall neural health.

McQuade 35


arthritic

animal studies

and tau protein concentrations decreased upon administration of these

or these drugs’ efficiency is still

Inhibition of γ-

McQuade 36

secretase would prevent cleavage of APP (and subsequent production of Aβ

oligopeptides).22

Although some progress has been made in recent years, a definitive treatment that

is viable for AD has not been proposed. Current treatments (such as NSAIDS and COX-2

inhibitors) are merely palliative, dealing only with disease symptoms rather than

addressing the root cause. Also, patient variability is another factor to be considered:

individuals respond to drugs differently because of various environmental and genomic

factors. Because molecular conditions vary so drastically between individuals, there is no

cure-all treatment for AD, just as there is no “silver bullet” to defeat cancer.102

If

Alzheimer’s is to be cured, a drug (or drug regimen) must be found to deal with the

symptoms while also attacking the root cause of the disease. Current medicinal methods

of treatment (although possibly delaying AD onset) do nothing to prevent neural damage

and cannot ultimately save the patient.90

Against the background of failed medicinal

treatments, turmeric emerges as a novel therapeutic compound that may prove highly

efficient in preventing and permanently curing AD. The therapeutic values of turmeric as

well as common critiques against its efficiency will now be evaluated in greater detail

Turmeric Absorption & Bioavailability

Turmeric is often critiqued for its poor bioavailability levels, especially in elderly

test subjects.103

This is an expected phenomenon: phenolic ring systems and their

associated hydrocarbon chains in curcumin are not easily dissolvable in the aqueous

plasma solution.104

Although the hydroxyl and ether groups are water-soluble, these

represent a very small portion of the curcumin molecule. Also, research suggests that

metabolism of turmeric occurs too quickly to produce healthful effects.105

Phenolic

groups have traditionally been viewed as relatively inactive. Often found in flowers,

fruits, nuts, and roots, phenols have been seen as unimportant to overall wellbeing.

Recently, however, researchers have found that these groups may play essential roles in

stopping cancer, protecting against oxidative damage, and preventing inflammation.106

In

fact, they may prove especially important in brain and liver health. Phenols strongly lend

McQuade 37

electrons and form sturdy intermediates due to hyperconjugation of their aromatic

systems.107

This provides them with a high degree of chemical stability. Some studies

suggest that a turmeric regimen supplemented with probiotics may produce enhanced

curcumin absorption from the stomach.108

When turmeric is obtained and freshly ground,

it is often accompanied by lactic acid bacteria (LAB) that aid substantially in its

metabolism and eventual digestion. In one study, a ferric-reducing antioxidant power

(FRAP) assay was used to determine the degree to turmeric (in the presence of LAB)

counteracted ROS.3 Rats were given a turmeric-containing solution that was fermented

with LAB. These rats demonstrated much higher absorption levels than humans who

imbibed turmeric without LAB. This finding suggests that therapeutic turmeric should be

as fresh as possible (so it contains LAB), or should be fortified with LAB probiotics.109

Also, like most other compounds, turmeric is best absorbed when ingested with a meal.

This leads to greater production of bile salts within the small intestine that can help

emulsify water-insoluble portions of curcumin.110

Certainly, future studies are needed to

elucidate optimal methods of turmeric delivery. Also, to date no studies have been

conducted regarding optimal dosage of turmeric for mammalian systems. Although many

of turmeric’s molecular mechanisms still remain hazy, substantial evidence supports the

hypothesis that turmeric will prove an effective therapeutic for AD.

Curcumin—A Therapeutic Solution

Turmeric (Curcuma longa) is a plant grown in much of southeast Asia.

Especially common in India, it is related to the ginger family and its dried rhizomes

are usually consumed as a spice.111 Turmeric is a yellow-brown color and exhibits a

mildly spicy taste. As a diarylheptanoid molecule, curcumin (diferuloylmethane) exists as

a substituted heptene chain flanked by two substituted benzene molecules.106

Curcumin is

categorized as a beta-diketone molecule, which lends special chemical and medicinal

activities. These phenolic groups contribute to turmeric’s brown-yellow color. As a

racemic molecule, it exists in both keto and enol forms.108

The enol form exists in higher

concentrations since it is more energetically favorable. In Curcuma longa, curcumin’s

biochemical production uses phenylalanine as a starting reactant. Turmeric contains over

McQuade 38

20 bioactive molecules, of which curcumin occupies approximately 3% of all turmeric’s

biomolecules.112

Circuminoids exist as three major forms: diferuloylmethane,

demethoxycurcumin, and bisdemethoxycurcumin. The first of these, diferuloylmethane,

is the circuminoid found in turmeric. Turmeric has been evaluated in many different

studies. One study measured the effects of suberoylanilidehydroxamic acid (SAHA) and

curcumin used together on Aβ plaques.113

Used in tandem, they were found to increase

learning and memory in transgenic rat models.113

Also, both these compounds were

discovered to protect neurons from the toxic effects of soluble and insoluble plaques. In a

separate study, researchers demonstrated that BDMC33 (a modified form of curcumin)

prevented the production of nitric oxide among macrophage cells, thus partially inhibiting

inflammation among body systems.114

PGs are common cellular components that are

naturally manufactured by nearly every cell type. They are made from AA and serve as

important lipid-derived secondary messengers in the body. As a vitally important PG, the

E2 variety is chiefly modulated by COX, which is also known as prostaglandin

endoperoxide H2 (PGH2) synthase.115

Current research has uncovered three major COX

molecules. Under normal conditions, COX-1 is active without any form of enzymatic

stimulation. COX-2, on the other hand, is inducible and is upregulated by the presence of

cytokines, cancer-stimulating genes, and various growth factors. Although not thoroughly

understood, COX-3 was found to possess intron-1. Researchers found that cellular

overexpression of PGE2 and COX-2 lead to a number of diseases, such as asthma,

arthritis, and AD—all related to pro-inflammatory activity.116

In multiple studies,

turmeric was found to prevent biological synthesis of PGE2. NSAIDS are designed to

specifically block pain caused by inflammatory disorders. COX-1 plays vital roles in

protecting the GI tracts, so researchers must be careful that NSAIDS do not block this

activity as well. Turmeric therapy solves this problem by effectively inhibiting PGH2

synthase (COX-2) activity, while not interfering with the normal homeostatic role of

COX-1.117

Figure 8 shows the pharmaceutical production of BDMC33. Notice that the

basic cyclical structure of curcumin is conserved and that a number of oxygen atoms with

lone-pair electrons (in the methoxy and carbonyl groups) are present.

BDMC33 in particular was found to stop nitric oxide synthesis from IFN

macrophages.114

Also, it partially inhibited COX

acts against free radical species that can cause major damage within the body.

the intermediary activity of curcumin, ROS could damage neural proteins, fats,

genetic sequences.111

Left unchecked, free radical species ultimately lead to

carcinogenesis or widespread apoptosis.

curcumin is able to “catch” free

neural tissue.116

Entrapment of metal ions like copper and iron prevents activation

NF-B pathway, thereby inhibiting

In multiple studies, curcumin has also been shown to

through downregulation of eicosanoid molecules, both in

bloodstream.53

In fact, curcumin

in many Eastern cultures.118

Ingestion of turmeric causes greater vasodilation (

produces the same health effect caused by an aerobic workout). In fact, when

amounts of turmeric ingestion is paired with aerobic exercise, results are markedly

improved.103

Thus, the potential benefits of aspirin in preventing inflammation are

miniscule compared to curcumin’s potent effects. It is critical that future studi

turmeric’s effect on swelling and blood pressure in greater detail.

Figure 8: BDMC33’s basic molecular structure. Notice that

its chemical preparation comes from addition of ethanol and a

strong base to cyclohexanone and a methoxy

benzaldehyde. The resulting product is a symmetric ketone

molecule that exhibits many medicinal effects.

McQuade

Curcumin analogues are especially

adept at preventing tumor activation,

excessive blood vessel growth, and

eicosanoid-stimulated inflammation.

BDMC33 in particular was found to stop nitric oxide synthesis from IFN- γ/LPS

Also, it partially inhibited COX-2 and PGE2 activity. Additionally, it

acts against free radical species that can cause major damage within the body.

the intermediary activity of curcumin, ROS could damage neural proteins, fats,

Left unchecked, free radical species ultimately lead to

carcinogenesis or widespread apoptosis. Also because of its unique molecular structure,

“catch” free-floating metal ions, thus preventing them from damaging

Entrapment of metal ions like copper and iron prevents activation

inhibiting production of Aβ plaques.78

In multiple studies, curcumin has also been shown to decrease inflammation

through downregulation of eicosanoid molecules, both in neural tissues and in the

In fact, curcumin is also known as an effective blood pressure medication

Ingestion of turmeric causes greater vasodilation (

produces the same health effect caused by an aerobic workout). In fact, when

turmeric ingestion is paired with aerobic exercise, results are markedly

the potential benefits of aspirin in preventing inflammation are

d to curcumin’s potent effects. It is critical that future studi

turmeric’s effect on swelling and blood pressure in greater detail.

BDMC33’s basic molecular structure. Notice that

its chemical preparation comes from addition of ethanol and a

strong base to cyclohexanone and a methoxy-substituted

benzaldehyde. The resulting product is a symmetric ketone

inal effects.

McQuade 39

urcumin analogues are especially

adept at preventing tumor activation,

excessive blood vessel growth, and

stimulated inflammation.

/LPS

Additionally, it

acts against free radical species that can cause major damage within the body. If not for

the intermediary activity of curcumin, ROS could damage neural proteins, fats, and

ecause of its unique molecular structure,

floating metal ions, thus preventing them from damaging

Entrapment of metal ions like copper and iron prevents activation of the

decrease inflammation

neural tissues and in the

is also known as an effective blood pressure medication

Ingestion of turmeric causes greater vasodilation (which

produces the same health effect caused by an aerobic workout). In fact, when moderate

turmeric ingestion is paired with aerobic exercise, results are markedly

the potential benefits of aspirin in preventing inflammation are

d to curcumin’s potent effects. It is critical that future studies examine

McQuade 40

By modulating key molecular players early in the pathway of amyloidogenesis,

curcumin therapy cuts straight to the heart of the issue. It precisely targets vital molecular

messengers like PGH2 and COX-2, directly impacts excessive enzyme activity by

targeting PLA2 and ceramide, and prevents ROS damage.93

Unless taken in exorbitantly

high doses (> 1 kg) intravenously, curcumin poses no known threats to body systems.106

Excessive ingestion of turmeric merely leads to discoloration of feces and diarrhea

without any other known complications.112

Compared to the side effects of COX-2

inhibitors (which can cause severe indigestion, insomnia, and headaches), the secondary

effects of turmeric are virtually nonexistent when taken in normal amounts. Rather than

attempting to treat AD symptoms, curcumin delves to the source of the problem by

stopping APP’s production of Aβ peptides.109

It also plays a modulatory role through

precise mediation of lipid catabolism pathways. Multiple studies show that curcumin

lowers inflammation, disposes of ROS, and prevents accumulation of plaques. It is also

suspected to inhibit a wide variety of cancers. Demographics that consume high amounts

of turmeric tend to demonstrate lower rates of Alzheimer’s. Although demographics

cannot conclusively prove that a curcumin-rich diet is responsible for a healthful

phenotype, this correlation cannot be overlooked in light of previous data.106

Turmeric demonstrates considerable medicinal activity for treatment of oncogenic

activity.111

In one study, murine macrophage RAW264.7 cells and HT-29 carcinogenic

human colon cells were both tested to determine turmeric’s effect on lipid cascade

activity and its impact on concentrations of select proteins. Cystolic phospholipase A2

(cPLA2) levels were measured as wells as COX and 5-lipoxygenase (5-LOX).106

First,

cells were activated using lipopolysaccharides (LPS), which upregulated COX-2

production. Tetrahydrocurcumin (THC) and curcumin both exerted an inhibitory effect

on the AA cycle so that AA was not liberated to produce pro-inflammatory eicosanoid

molecules.3 It seems that this was largely due to prevention of cPLA2 phosphorylation.

The enzyme itself was not inhibited; rather, activation through phosphorylation was

prevented. This is an important distinction because it means that curcumin did not knock

out total enzyme function. Even in the presence of curcumin and THC, cPLA2 was still

able to conduct its normal activities, but without excessive phosphorylation. Every

curcuminoid tested in this study caused lower levels of prostaglandin E (PGE2). Thus,

curcumin proves itself to be a potent COX inhibitor. It is used in treating many cancer

types as well as gastrointestinal problems. It also acts against free radical species that can

Through the mediatory activity of curcumin, turmeric effectively addresses all the

major issues caused by AD—

addresses PLA2, reduces the acti

genes, and targets TNF-α. Its concise

plaques and the dissolution of NFTs

Figure 9: Curcumin shown in its diketone and enol forms.

Curcumin’s biological ability to tautomerize lends greater

stability to the molecule and provides a wider range of

medicinal applications.

McQuade

itself to be a potent COX inhibitor. It is used in treating many cancer


cause major damage within the body

and can protect neurons from

environmental toxins and also

endogenous factors.


—both the internal environment and at the genomic level. It

, reduces the activity of ROS, prevents excessive methylation of key

Its concise modulatory activity is crucial for terminating A

plaques and the dissolution of NFTs—essentially curing Alzheimer’s.

Curcumin shown in its diketone and enol forms.

Curcumin’s biological ability to tautomerize lends greater

stability to the molecule and provides a wider range of

McQuade 41

itself to be a potent COX inhibitor. It is used in treating many cancer


e major damage within the body

and can protect neurons from

environmental toxins and also


both the internal environment and at the genomic level. It

vity of ROS, prevents excessive methylation of key

terminating Aβ

Figure 10 shows the multiple methods by which curcumin modulates molecular factors

Figure 10: Therapeutic roles of turmeric. As

section, curcumin directly impacts secretase, presenilin, GSK

3β activity and also provides increased neural protection

against exogenous metals, tau proteins, and extracellular

plaques.

McQuade

shows the multiple methods by which curcumin modulates molecular factors

Therapeutic roles of turmeric. As outlined in this

section, curcumin directly impacts secretase, presenilin, GSK-

activity and also provides increased neural protection

against exogenous metals, tau proteins, and extracellular

McQuade 42

shows the multiple methods by which curcumin modulates molecular factors

McQuade 43

involved in AD ontology and progression. Turmeric offers a safer and more effective

treatment than NSAIDS, cholinesterase inhibitors, or anti-inflammatory medications.108

Future studies must investigate the role of turmeric paired with other therapeutic

compounds, such as liquiritin, CP, and shankhpushpi. To date, several studies have

underscored the importance of CP and liquiritin, but none have ever investigated

potential synergistic effects when used in tandem.119

Prospects for Future Studies

Study Purpose: The main purpose of this study is to determine the efficacy of turmeric

for the treatment of AD. Hence, the aims of this prospective study are two-fold. First, this

study will determine turmeric’s impact on amyloid-β plaque deposition in transgenic AD

models in very early stages of the disease. Secondly, it will determine the effect of

turmeric on improvement of spatial learning, coordination, and balance in stage 2

Alzheimer mice.

Experimental Design: This study will be preformed across a span of six months using a

total of 100 test subjects (Mus musculus) divided into four groups. Results from each

group will be collected on a daily basis. This study will be performed during a period

of six months using a total of 100 test subjects (Mus musculus) divided into four

groups. Results from each group will be collected on a daily basis. Before beginning

the study, all mice (AD and healthy) will be pre-screened to measure blood pressure,

coordination and balance, etc. Conduct brain scans of normal mice and Stage 1

transgenic Alzheimer mice. Scans measuring brain activity between the two groups

will be compared and evaluated. Four groups will be created (each containing 25

subjects)

1). Group A1 will consist of healthy mice that consume standard lab-grade rodent

feed.

McQuade 44

2). Group A2 will consist of healthy mice that consume a mixture of standard lab-

grade rodent feed with 5 mg/kg of freshly ground turmeric added. Two grams of

turmeric will be added to every liter of water.

3). Group B1 will contain Alzheimer’s mice and will only consume lab-grade rodent

feed.

4). Group B2 will contain Alzheimer’s mice, but will consume lab-grade feed with 5

mg/kg of turmeric added to food and 2 grams of freshly ground turmeric added per

liter of drinking water. Each mouse will receive its own separate cage with

individual food and water. Amount of food/water consumed will be measured and

appropriated for each mouse. All other elements besides food will be kept as

constant as possible. SMase activity will be closely monitored (both acidic and basic

forms). Plasma levels of SMase and a fluorescent assays will be used to collect

enzyme activity. COX-2 activity will be measured as well as reactive oxygen species

(ROS). Enzyme activity will be determined using Michaelis-Menten kinetics and

evaluated appropriately. Enzymes in blood serum and CSF will also be collected and

measured. PLA2 and ceramide activities will be evaluated for each of the four

groups. Data will be statistically evaluated using appropriate parameters.

Mice will be tested periodically every 2 weeks and be subject to a variety of

balance/strength/coordination tests. Rotarod test Morris water navigation task, the

grip test meter test, maze tests, and a balance beam will all be used. All results will

be evaluated using appropriate statistical methods. Extensive collection of data will

be conducted throughout the course of the experiment. After a period of six months,

all mice will be sacrificed and overall brain appearance will be evaluated by a team

of researchers. Brains will be tested for plaques, lesions, demyelination, tissue

shrinkage, or any other pathological or abnormal signs.

Necropsy: After 60 days, all subjects will be terminated via CO2 asphyxiation and a

necropsy will be preformed to determine the degree to which amyloid-beta plaques have

accumulated in the brain.

McQuade 45

Hypothesis: Mice consuming a turmeric-containing diet will demonstrate lowered

susceptibility to development of AD. Also, AD mice on the turmeric diet will show fewer

motor/coordination abnormalities than the AD group that did not receive turmeric.

Prevention of Unnecessary Pain: If mice display intense pain or suffering, they will be

terminated humanely using CO2 asphyxiation.

Problems/Obstacles: The most probable foreseen obstacle in this study is whether

positive results can be pinpointed to turmeric’s medicinal activity or due to some other

unforeseen factor. Although a quantitative evaluation of results will be conducted, this

study cannot rule out some other confounding factor that influenced turmeric’s activity.

Also, it is unknown whether some component of the lab-grade rat feed exerts a

beneficial/negative effect upon turmeric’s activity, both through absorption in the

bloodstream and activity in the nervous system. Although environmental factors can be

carefully manipulated, there is no guarantee that all conditions for every group will be

equivalent.

Significance of Study: Many researchers suspect that turmeric possesses incredible

potential as a medicinal chemical compound. This must be determined experimentally

before turmeric is implemented in a hospital or clinical setting. The future of turmeric as

a healthful compound is dependent upon this study and other related investigations.

Future Directions: Avenues of future research are largely contingent upon experimental

results. If the turmeric-fed mice exhibit retardation of AD progression, future research

should determine turmeric’s optimal dosage for Alzheimer’s patients. Although

investigating this issue to some extent, this current study will not elucidate all details of

effective drug regimen. Also, future studies must determine if turmeric is best taken alone

or in combination with another compound. In particular, CP and liquiritin are two

compounds are special interest Methods will be suggested as to certain novel compounds

that can be screened for medicinal efficiency. Many current studies complain that

turmeric is poorly absorbed because of its relatively poor solubility in water.

McQuade 46

Discussion

As multiple studies demonstrate, NSAIDs can mediate immune response, but they

do not effectively reduce Aβ plaques.10

Although well-intentioned, current drug designs

suffer from a fundamental flaw in their production-- they are derived largely from

empirical methods and do not usually begin with a presuppositional framework in mind.

This directly leads to the treatment of specific disease symptoms (COX-2 reduction,

thromboxane inhibition, etc.) without targeting the basic cause of the disease. Since these

therapies are limited in scope, they also demonstrate numerous secondary effects, some

of which are deadly. Although offering great potential, memantine suffers from short-

term activity as neural receptors quickly accommodate. Likewise, lithium fails to offer

consistently reliable results (and also demonstrates mixed experimental results). Lithium

has also garnished concern over its potentially toxic effect to body organs.95

Therefore,

neither lithium nor memantine can be employed for patient care or for any kind of long-

term treatment. In contrast to pharmaceutical compounds, turmeric offers a wide range of

healthful effects. Despite some studies that demonstrate poor solubility, research has

determined that fortification with LAB significantly increases turmeric’s bioavailability.

This finding suggests that turmeric used for AD therapy should be intentionally grown in

the presence of LAB and should be consumed in the freshest form possible. Further

studies must verify and add further details regarding how LAB increases curcumin’s

effectiveness.

The proposed turmeric study will elucidate further details about how turmeric

impacts AD murine models. Adjusting for any confounding factors, these findings can be

directly applied to human patients. Based on current research, it is hypothesized that

turmeric ingestion will greatly increase cognition and memory and also boost

coordination and muscle control. Future studies will investigate dosage considerations

and whether turmeric is best used in combination with other compounds or taken by

itself. Other transgenic model organisms will be tested to determine if turmeric’s effects

are confined to one species or can impact many different species. It is presumed that the

latter scenario will be proven correct and that each organism will utilize similar cascades

and molecular mechanisms in metabolism of turmeric.

McQuade 47

Conclusion

Despite the valiant efforts of researchers and physicians, AD still remains an

incurable and deadly disease. Impacting millions around the world each year, it is

especially prevalent in America and Europe and targets the elderly demographic.81

AD is

a complex, multifactorial disease that is typified by external Aβ plaques and internal

NFTs (due to faulty secretase cleavage of APP and excessive tau phosphorylation

respectively).20

Historically, the Homo sapiens genome has always displayed a potential

for AD development; widespread Alzheimer’s, however, is a relatively recent

phenomenon due to longer lifespans and harmful environmental factors.13

It is

hypothesized that upregulation of inflammatory cascades (driven by AA and ceramide

production) are the major stimulant in driving disease pathology.74

A complex interplay

of diet, gene expression, and organism variability is implicated in this process. It is

believed that this internal inflammation provides the motive force behind SP and NFT

accumulation. By means of a vicious cycle, even the body’s own immune response

stimulates disease conditions through microglial activation.85

Likewise, the “cytokine

storm” produced by AA and ceramide pathways only increase inflammation, caspase

activity, and cell necrosis. Multiple drug regimens have been developed for treating AD,

but so far are only mildly effective (or even detrimental in many cases). Although

demonstrating some potential, COX-2 and cholinesterase inhibitors are not yet suitable

for patient use and their efficacy in treating AD is doubtful.87

Even NSAIDs (perhaps the

most effective of AD therapeutics) and memantine are extremely time-dependent, and

their usefulness rapidly declines with each use.10,88

In the absence of a useful AD

therapeutic, researchers are desperately searching for novel compounds that produce

clinical results. As multiple studies show, the burden of evidence weighs heavily on

turmeric, warranting the need for further clinical and experimental investigations.3,105,106

It is hoped that turmeric will turn the tide of disease progression and restore cognitive,

learning, and STM functions.16

Additionally, a turmeric-based drug regimen will inhibit

neuroinflammation by retroactively preventing exorbitant eicosanoid expression by

deactivation of PGH2 synthase (COX-2).114

Although most neural damage is irreversible,

curcumin will demolish existent Aβ plaques, unravel NFTs, and prevent apoptotic

McQuade 48

activity.118

It is tantamount that turmeric therapies be administered in the earliest stages

of the disease since this promises the greatest chance of a full recovery. These

conclusions will be investigated further in the “Proposed Study” section, which will test

how turmeric affects motor skills, coordination, and balance of transgenic Alzheimer

mice. Because of its widespread effects in targeting SPs and NFTs, impacting AA and

sphingomyelinase cascades, and halting ROS, turmeric warrants incorporation into

Western medicinal practice. It is hoped that turmeric may be used in tandem with another

medicinally useful compounds (natural or synthetic) to ebb the tide of AD.108

Of all

potential therapies, turmeric will halt the Alzheimer epidemic and its ravaging grip on

Western society.

McQuade 49

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