Alzheimer’s Disease Gavin Mast, Musa Abdus-Samad, Arash Rezaeian, Sarah Rocha PHM142 Fall 2015 Instructor: Dr. Jeffrey Henderson.
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Alzheimer’s DiseaseGavin Mast, Musa Abdus-Samad, Arash Rezaeian,
Sarah Rocha
PHM142 Fall 2015Instructor: Dr. Jeffrey Henderson
Signs and Symptoms• Memory Loss
• Difficulty in problem solving
• Challenges in completing basic tasks
• Confusion in time or place
• Difficulty with visual and depth perception
• Struggling with conversation and vocabulary
• Poor judgement for basic decision-making
• Withdrawal from work or social activities
• Changes in personality
Types of Alzheimer’s Disease
1- Early-onset Alzheimer’s: diagnosed in individuals under the age of 65 and may be linked with a genetic defect (Chromosome 14 or Trisomy 21).
2- Late-onset Alzheimer’s (Sporadic): diagnosed in individuals over the age of 65; researchers have not linked this to any genetic factors.
3- Familial Alzheimer’s Disease (FAD): the disease that researchers have proved is linked to a genetic disorder in which at least two generations have the disease. Individuals may start to show symptoms as early as in their 40s.
Amyloid Cascade Hypothesis
Enzymes
● β & γ secretase: converts APP to Aβ monomers● α secretase● Neprilysin, Insulin degrading enzyme (IDE) &
Apolipoprotein E (ApoE): Degradation of Aβ
Production of amyloid plaques:
Amyloid precursor protein (APP) → Aβ(1–40) & Aβ(1–
42) → Oligomers → Plaques
Effects
Toxic oligomers → alterations in synaptic proteins → synaptic dysfunction & neuronal cell
death → Brain dysfunction & Dementia
Genetic factors:Familial genesMutations in these genes are known to cause the disease in 5% of patients
● APP: Preferential processing of APP → Amyloid β
● PSEN1 & PSEN2: increased likelihood of Aβ(1–42) production
● SorL1: Decreased degradation of Amyloid β
Tau and Neurofibrillary Tangles
• Tau is a microtubule associated protein (MAP) primarily found in neurons
o Interacts with tubulin to stabilize microtubules of cytoskeleton
• Hyperphosphorylation of tau results in loss of biological activity and altered conformation
o Leads to Paired Helical Fibres (PHFs) and subsequently aggregates as Neurofibrillary Tangles (NFTs)
Causes and Effects of NFTs• How tau becomes hyperphosphorylated is still not fully understood:
o Overactivity of kinases (GSK-3β, Cdk5)
o Inhibition of phosphatases
o Other post-translational modifications may occur
• Formation of NFTs results in destabilization and degradation of neuronal microtubules
o Impaired axonal transport and eventual synaptic loss
Associated with memory loss found in AD
o Number of NFTs correlates well with disease progression
Other Mechanisms Contributing to the Progression of Alzheimer's Disease
Dysfunction of Autophagy
• Failure to remove protein aggregates from the cytosol
• ER stress caused by protein aggregates results in activation of apoptotic pathways and neuron death
Oxidative Stress
• Increased ROS in neurons leads to protein oxidation, DNA and mtDNA oxidation, and lipid oxidation
• HNE → neuronal cytotoxic lipid oxidation product that interferes with the function of membrane proteins (e.g. GLUT1/3 transporters, Na/K-ATPase, etc.)
Current Alzheimer’s Disease Treatments
Cholinesterase Inhibitors
Donepezil, galanatamine, reivastigmine, and tacrine
• Increase ACh concentrations within the synaptic cleft to increase neuron-to-neuron signalling
NMDA Receptor Antagonists
Memantine
• Competitively binds NMDA receptor to prevent glutamate-induced neuronal excitotoxicity
Possible Therapies
1. Regulators of APP proteolysis• 𝛽-secretase inhibitors
2. Increasing amyloid- degradation 𝛽• Neprilysin gene therapy
3. Tau aggregation inhibitors
Summary Slide• Alzheimer’s is a chronic neurodegenerative disease and most common form
of dementia, with no currently understood cause for majority of cases
• APP is cleaved by β- and ɣ-secretases into Aβ, which aggregates to form neurotoxic oligomers and plaques within the brain
• Tau microtubule associated protein becomes hyperphosphorylated in AD leading to formation of neurofibrillary tangles and loss of synaptic connections
• Other effects include dysfunctional autophagy and increased oxidative stress within neurons
• Current treatments include cholinesterase inhibitors and NMDA antagonists
• Future therapies focus on inhibition of mechanisms associated with Aβ and NFTs
References Amemori, T., Jendelova, P., Ruzicka, J., Urdzikova, L. M., & Sykova, E. (2015). Alzheimer’s Disease: Mechanism and Approach to Cell
Therapy.International journal of molecular sciences, 16(11), 26417-26451.
Crews, L., & Masliah, E. (2010). Molecular mechanisms of neurodegeneration in Alzheimer's disease. Human molecular genetics, ddq160.
Feng, Y., & Wang, X. (2012). Antioxidant Therapies for Alzheimer ’ s Disease, 2012. doi:10.1155/2012/472932
Kolarova, M., García-Sierra, F., Bartos, A., Ricny, J., & Ripova, D. (2012). Structure and pathology of tau protein in Alzheimer disease.
International journal of Alzheimer’s disease, 2012.
Krohn, M., Bracke, A., Avchalumov, Y., Schumacher, T., Hofrichter, J., Paarmann, K., ... & Pahnke, J. (2015). Accumulation of murine amyloid-β
mimics early Alzheimer’s disease. Brain, awv137.
Li, Y., Wang, J., Zhang, S., & Liu, Z. (2015). Mini-Review Neprilysin Gene Transfer : A Promising Therapeutic Approach for Alzheimer ’ s
Disease, 1329, 1325–1329. doi:10.1002/jnr.23564
Sakamoto, S., Ishii, K., Sasaki, M., Hosaka, K., Mori, T., Matsui, M., ... & Mori, E. (2002). Differences in cerebral metabolic impairment between
early and late onset types of Alzheimer's disease. Journal of the neurological sciences,200(1), 27-32.
Wischik, C. M., Harrington, C. R., & Storey, J. M. D. (2014). Tau-aggregation inhibitor therapy for Alzheimer ’ s disease. Biochemical
Pharmacology, 88(4), 529–539. doi:10.1016/j.bcp.2013.12.008
Yan, R., & Vassar, R. (2014). Targeting the β secretase BACE1 for Alzheimer ’s disease therapy. The Lancet Neurology, 13(3), 319–329.
doi:10.1016/S1474-4422(13)70276-X
Zhu, X., Yu, J., Jiang, T., & Tan, L. (2013). Autophagy Modulation for Alzheimer s Disease Therapy, (April), 702–714. doi:10.1007/s12035-013-
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