Alzheimer’s Disease Gavin Mast, Musa Abdus-Samad, Arash Rezaeian, Sarah Rocha PHM142 Fall 2015 Instructor: 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 genes Mutations 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 -secretase inhibitors 2. Increasing amyloid- degradation 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

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