Alzheimer's Flashcards
What is the main risk factor?
age
What genes contribute to Alzheimer’s?
APEN, APP, ApoE
What are the symptoms of Alzheimer’s?
- Memory loss – short-term
- Disorientation/confusion
- Language problems – stops mid-conversation
- Personality changes – becoming confused, fearful, anxious
- Poor judgement – e.g. with money
What is the amyloid hypothesis?
Normal:
- Amyloid precursor protein (APP) cleaved by a-secretase
- sAPPa released and the C83 fragment remains
- C83 is then digested by y-secretase (gamma)
- Products are then removed
Pathophysiology:
- APP cleaved by b-secretase.
- sAPPb released leaving the C99 fragment
- C99 is digested by y-secretase releasing b-amyloid (Ab) protein.
- Ab protein forms the toxic aggregates
What is the tau hypothesis?
- Hyperphosphorylated tau is insoluble -> self-aggregates
- The self-aggregates form neurofibrillary tangles
- These are neurotoxic - The tangles result ultimately in microtubule instability and neurotoxic damage to neurones
What is tau protein?
a soluble protein present in axons - important for assembly and stability of microtubules
What is the inflammation hypothesis?
Microglial cells are specialised CNS immune cells (like macrophages)
Pathophysiology:
- Increased release of inflammatory mediators & cytotoxic proteins
- Increased phagocytosis
- Decreased levels of neuroprotective proteins
What anticholinesterases are used to treat AD?
Donepezil:
- Reversible cholinesterase inhibitor
- Long plasma T1/2
Rivastigmine:
- Pseudo-reversible anti-cholinesterase (AChE) & butyl-cholinesterase (BChE) inhibitor
- T1/2 = 8 hours
- Can be given as a transdermal patch
Galantamine:
- Reversible cholinesterase inhibitor
- T1/2 = 7-8 hours
- a7 nAChR agonist
What glutamate
(NMDA) receptor blocker is used?
Memantine:
- Use-dependant non-competitive NMDA receptor blocker with low channel affinity
- Treats moderate-> severe AD
- Long plasma T1/2
What are some failed/ non-current y-secretase inhibitors?
both failed clinical trials
- Tarenflurbil – binds to APP molecule
- Semagacestat – SMI of the y-secretase molecule
What are some failed/ non-current b-amyloid drugs?
Passive drugs:
- Bapineuzumab – antibody against Ab-protein
- Solanezumab – antibody against Ab-protein
Active drugs – in development:
- Vaccines
What are some failed/ non-current tau inhibitors?
in clinical trials
Methylene blue – currently treats methaemoglinanaemia
