Alzheimer's disease Flashcards
What factors contribute to the development of AD?
Environmental factors (90% of cases) Mutations in genes increase risk
What are 5 clinical symptoms of Alzheimer’s disease?
Memory loss: esp. recently acquired info
Language problems: stopping mid-sentence
Personality changes: confusion, fear, anxiety
Poor judgement: e.g. when dealing with money
Disorientation/confusion
What is the main risk factor of Alzheimer’s disease?
Advancing age
What classes of drugs are used to treat Alzheimer’s disease?
- Anticholinesterases
2. NMDA receptor antagonists
What are the 3 main theories regarding the underlying pathophysiology of AD?
- Amyloid hypothesis
- Tau hypothesis
- Inflammation hypothesis
What is the amyloid hypothesis?
- APP cleaved by β-secretase
- Soluble APPβ released, C99 fragment remains
3.C99 digested by γ-secretase releasing β-amyloid (Aβ) protein
Aβ = forms toxic aggregates on neurons + microvasculature
What is the tau hypothesis?
Hyperphosphorylated tau is insoluble+ self-aggregates to form neurotoxic intracellular neurofibrillary tangles
Also results in dissociation of tau from microtubules + microtubule instability
What is the inflammation hypothesis?
Microglia (specialised CNS immune cells) become activated in AD resulting in:
increased release of inflammatory mediators + cytotoxic proteins
increased phagocytosis
decreased levels of neuroprotective proteins
Compare the anticholinesterases used to treat AD
Donepezil: reversible cholinesterase inhibitor, long plasma half-life
Rivastigmine: pseudo-reversible AChE + BChE inhibitor, 8 hour half-life, reformulated as transdermal patch to counteract BChE inhibition side effects
Galantamine: reversible cholinesterase inhibitor, 7-8 hour half-life, α7 nAChR agonist (increases ACh available)
What type of drug is memantine? When is memantine used in AD?
NMDA receptor antagonist
Only in moderate to severe AD
Describe memantine
Use-dependent non-competitive NMDA receptor blocker
Low channel affinity
Long plasma half-life
What does normal physiological processing of the amyloid precursor protein involve?
- Amyloid precursor protein (APP) cleaved by α-secretase
- Soluble APPα released, C83 fragment remains
- C83 digested by γ-secretase
End-products of this pathways are non-toxic + removed
Describe the normal physiology of Tau
Tau = soluble protein associated w/microtubules in neurons
Involved in stabilisation + assembly
What molecules/ processes have been unsuccessful targets in AD?
Gamma secretase inhibitors (target both pathophysiological + physiological)
Antibodies against B-amyloid plaques
Tau inhibitors (reduce aggregation)