Therapeutic Target for Alzheimer’s Disease Tapan Audhya, PhD. New York University, NY, USA Health Diagnostics & Research Institute, NJ, USA [email protected]First International Congress on Updates and Advances in the field of Clinical Nutrition and Orthomolecular Medicine 2011, Valencia, Spain
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Advances in the field of Clinical Nutrition and ... · PDF fileClinical Nutrition and Orthomolecular Medicine 2011, Valencia, Spain. Types of Alzheimer Disease (AD) 1.Familial Alzheimer
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First International Congress on Updates and Advances in the field of
Clinical Nutrition and Orthomolecular Medicine2011, Valencia, Spain
Types of Alzheimer Disease (AD)
1.Familial Alzheimer Disease (FAD)
2.Early-onset Familial Alzheimer Disease (EOFAD)
3.Late-onset Alzheimer Disease (LOAD)
(sporadic Alzheimer Disease)
Cont….
FAD:a) Entirely inheritedb) Affected family members of at least two
generationc) Often starts at age 40’sd) Extremely rare 1-2% of total
Cont…
EOFAD: a) Autosomal Dominant Mutationb) Usually close to 160 mutation in chromosomes -1,
-14, -21, and 19 (APO€4)c) Virus infection in young aged) Increase in Aβ production e) Symptoms of disease appear before the age of 65 f) Approximately 10-20% of total AD are affectedg) Easily identified from muscle twitching and spasm
(myoclonus)h) Chronic Inflammation
Cont..LOAD:
a) Most common form, accounting for about 80%b) Usually show symptoms after age 65 and half of them
over 85c) May or may not be hereditaryd) Several polymorphic gene in this group has been
identified in chromosome-10 and 6e) Common symptoms are : Depression, CFS/ME, high
oxidative stress, defects in glucose and lipid metabolism, high Cortisol & glutamic acid.
f) Produce Aβ peptides and there is imbalance between Aβ production and clearance
g) Lack of B-vitamin, ω3 fatty acid & antioxidants. Low level of acetylcholine and high level of toxic chemical.
Methionine is in fasting conditionHS Cysteine is after dinner (meal) conditon
MTHFR Needs FAD. It is a dimer of 77k DA; each non covalently bound to FADRequire NADH for reduction.Km for NADPH is 16 umole/L
B12
and Km for CH2-THF is 88.0 μmole/L
Folate Metabolism: Alternate Pathways
Inosine
Uric acidB6
CBS
ATP
(methyltrap) Ring
Closure
Formyl transfercoenzyme
NADPH
Glycine +P-5-P+ serine-oH-methylase
ATP + HC00H+FH4Methyl
transferase
(FH4)
MSB12
Healthy Neuron Vs. Dying Neuron in Alzheimer
Pathological Features
Schematic Diagrams of the β-amyloid Precursor Protein (APP) and its Metabolic Derivatives
Measurement of β-amyloid (Aβ) Peptide• Aβ1- 42 Found in Neurotics plaques
It is hydrophobic and prone to aggregation• Aβ1- 40 More abundant than Aβ1- 42
• Both of these peptides and their auto-antibodies are found in CSF and plasma of normal, mild cognitive impaired (MCI), AD patients and their extended families.
• Beside brain, the peptides are present in various human tissues, such as, platelets, liver, skeletal muscles, kidney, lungs, skin, intestine and sc. tissue in ratio 90/10
• A transporter dependent movement is involved in transporting Aβ from CSF to plasma via interstitial fluid (ISF). Two such transporters are LRP-1* and RAGE*. Insulin helps the clearance of Aβ peptide from the brain.
LPR-1 – Low density lipoprotein receptor-related protein-1RAGE – Receptor for advanced glycation end products
Effect of Dissociation of Plasma Amyloid Protein
0
0.2
0.4
0.6
0.8
1
1.2
Control (N=35) AD (N= 23)
ControlAD
Effect of Dissociation of Plasma Amyloid Protein
Control (N = 35) AD (N = 25)
Before
After Before
After
Level of Plasma Aβ(1- 40) and Aβ(1- 42) of Geriatric Population with LOAD
20.6 – 30.8538 - 726
26.1 – 47.6240 – 407
30.3 – 51.6218 – 245
17.8 – 40.0187 – 212
14.2 – 21.6159 – 178
5.6 – 10.168 - 138
Pg/mlPg/ml
15.9 – 19.0177.6 – 200.23786 – 90
16.2 – 18.3167.2 – 180.64681 – 85
19.7 – 30.7153.4 – 177.94976 – 80
11.6 – 21.5130.2 – 166.66271 – 75
9.6 – 15.9110.6 – 135.62566 - 70
2.2 – 6.750.2 – 100.73160 - 65
Aβ(1- 42)Aβ(1- 40)NAge
Level of CSF Aβ(1- 40) and Aβ(1- 42) in Populationwith Different ADAS-cog Score
(ng/ml)(ng/ml)
Aβ(1- 40)
14.615.34237-52Severe
6.413.64530-35Moderate
18.114.24716 -28Mild
7.420.63910 -20Questionable
3.216.4410 -5Normal
Aβ(1- 42)NADAS-cogScore
Level of Plasma Aβ(1- 40) and Aβ(1- 42) &ADAS-cog Score
157.4 – 198.8643 – 128437-52Severe
187.6 – 251.3503 – 72130-35Moderate
142.7 – 192.3309 – 516 11-28Mild
54.6 – 81.4230-26810-20Questionable
8.2 – 15.7142-1590-5Normal
Aβ(1- 42)pg/ml
Aβ(1- 40)pg/ml
ADAS-cog Score
Level of Aβ Peptides in the Tissue of Frontal Cortex in AD Patient
(mean number of words not recalled)Orientation 0 - 8(one point for each incorrect response)Word Recognition 0 – 12(mean number of incorrect responses)Remembering test Instructions 0 – 5Language 0 - 25