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

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