Alzheimer's Disease Flashcards
What is the main risk factor for Alzheimer’s?
- Age
Describe the genetic component to Alzheimer’s - 3 genes
- APP – mutations in the amyloid precursor protein → early onset of Alzheimer’s disease
- PSEN – mutations in presenilin gene → increase likelihood of early onset Alzheimer’s disease
- ApoE (8%) – Apo Lipoprotein E mutation → increased likelihood of late onset Alzheimer’s
List the clinical symptoms of Alzheimer’s disease
- Memory loss – especially recently acquired information – MOST PROMINENT SYMPTOMS
- Disorientation/confusion – forgetting where they are
- Language problems – stopping in the middle of a conversation
- Personality changes – becoming confused, fearful, anxious
- Poor judgement – such as when dealing with money
Outline the beta-amyloid hypothesis for Alzheimer’s disease
- There is normal physiological processing of APP (amyloid precursor protein) but this goes pathological resulting in beta-amyloid aggregates which are toxic
PHYSIOLOGICAL PROCESSING
- APP cleaved by α-secretase releasing sAPPα but C83 fragment remains
- C83 then metabolised by γ-secretase and the products are cleared
PATHOPHYSIOLOGICAL PROCESSING
- APP cleaved by β-secretase releasing sAPPβ but C99 fragment remains
- C99 then metabolised by γ-secretase releasing beta-amyloid protein
- Forms a toxic beta-amyloid plaque
Outline the Tau hypothesis for Alzheimer’s disease
- Tau is a soluble protein in neuronal cell cytoskeletons important in microtubule assembly and stability
- Pathophysiology: Hyperphosphorylated Tau is insoluble and self-aggregates to form neurofibrillary tangles which are neurotoxic - results in microtubule instability
Outline the inflammation hypothesis for Alzheimer’s disease
- Microglia are basically like neural macrophages
PATHOPHYSIOLOGY
- Inappropriate activation of microglial cells
- Increased release of inflammatory mediators and cytotoxic proteins
- Increased phagocytosis
- Decreased levels of neuro-protective proteins
What are the functions of microglia in the brain?
- Phagocytic role
- Secrete inflammatory mediators
- Neuro-protective role
What are the 2 types of drugs used to treat Alzheimer’s?
- Anticholinesterase
- NMDA receptor blocker
Give the 3 anticholinesterase drugs used for treating Alzheimer’s and expand on their mode of action
- Donepezil
* Reversible cholinesterase inhibitor - Rivastigmine
* Pseudo-reversible AChE and BChE inhibitor - Galantamine
- Reversible cholinesterase inhibitor
- Also direct alpha-7 nAChR agonist
Why is there an adverse side effect profile with Rivastigmine?
- Rivastigmine is a pseudo-reversible AChE and BChE inhibitor
- BChE is both present in neural tissue but also in liver tissue, it is a liver enzyme so it causes far ranging side effects
Give the name of one NMDA receptor blocker used to treat Alzheimer’s and give its mode of action, also in particular who is it prescribed for?
- Memantine
- Use-dependent non-competitive NMDA receptor blocker with low channel affinity
- I.e. the more the NMDAr receptors are activated, the more likely memantine is to have an inhibitory effect
- Only prescribed for people with moderate to late stage alzheimer’s
Give 3 examples of Alzheimer’s treatment failures in terms of the type of drug / mode of action, and give some named examples where possible
- Gamma-secretase inhibitors
- Tarenflurbil
- Semagacestat
- Beta-amyloid monoclonal antibodies (target beta-amyloid plaques)
- Bapineuzumab
- Solanezumab
- Tau inhibitors
* Methylene blue
1) Give more detail on the mode of action of Tarenflurbil & Semagacestat
2) Why is Semagacestat actually dangerous?
1)
- Tarenflurbil - gamma secretase inhibitor that binds to the amyloid precursor protein (APP) molecule
- Semagacestat - small molecule g-secretase inhibitor
2)
- Causes skin cancer – inhibits the NOTCH pathway
