25. Alzheimer's disease Flashcards
what is the main risk factor for Alzheimer’s disease?
age
what are the genetic components to Alzheimer’s?
- mutations in the amyloid precursor protein (APP) –> early onset
- mutations in presenilin gene (PSEN) –> increased likelihood of early onset
- Apo Lipoprotein E (ApoE) mutation –> increased likelihood of late onset
what are the clinical symptoms of Alzheimer’s disease?
- memory loss (especially recently acquired information)
- disorientation/confusion
- language problems
- personality changes
- poor judgement
what is the beta amyloid hypothesis of Alzheimer’s?
there is an accumulation of beta amyloid plaques within the brain/CNS
how should APP be processed?
- APP is cleaved by a-secretase
- sAPP-alpha is released but the C83 fragment remains
- C83 is digested by gamma-secretase and the products are removed
how does the beta-amyloid hypothesis suggest APP is processed in Alzheimer patients?
- APP in cleaved by b-secretase
- sAPP-beta is released but the C99 fragment remains
- C99 is digested by gamma-secretase, releasing b-amyloid protein
- b-amyloid protein forms toxic aggregates –> formation of beta-amyloid plaques
what is Tau protein and why is it important?
a soluble protein present in neuronal axons - forms the internal skeleton of neuronal cells
it is important for the assembly and stability of microtubules
what is the Tau hypothesis of Alzheimer’s?
hyper-phosphorylated Tau is insoluble –> self aggregates to form neurofibrillary tangles
these are neurotoxic –> results in microtubule instability
what are microglia?
specialised CNS immune cells - similar to macrophages
what is the inflammation hypothesis?
- inappropriate activation of microglial cells
- increased release of inflammatory mediators and cytotoxic proteins
- increased phagocytosis
- decreased levels of neuro-protective proteins
what 2 categories of drugs do Alzheimer drugs fall into?
- anticholinesterases
- NMDA receptor blocker
list the 3 anticholinesterase drugs and outline their key features
- donepezil
- reversible cholinesterase inhibitor
- long plasma life - pseudo-reversible AChE/BChE (butyrylcholinesterase) inhibitor
- short half life
- reformulated as transdermal patch formulation - Galantamine
- reversible cholinesterase inhibitor
- short half life
what does inhibition of butyrylcholinesterase enzyme lead to?
side effects such as liver problems
what is the NMDA receptor blocker used to treat Alzheimer’s disease and what are its key features?
Memantine
- only licensed for moderate/severe Alzheimer’s
- use-dependent non-competitive NMDA receptor blocker with low channel affinity
- the more the NMDAr is activated, the more likely memantine is to have an inhibitory effect
- long plasma half-life
list 3 treatment failures for Alzheimer’s
- gamma-secretase inhibitors
- monoclonal antibodies for b-amyloid proteins
- Tau inhibitors
