25: Alzheimer's disease Flashcards
What are the main risk factors for developing Alzheimers disease
There are two types
- No known cause, risk factor: Age
- RARE: genetic mutations leadin to predisposition to early onset Alzheimers (only 8%)
–> Main risk factor age
What are the sympotms of alzheimers diesee?
Mainly: Memory loss (expecially recently aquired information) +
- change in personality
- disorientation
- language difficulties (stoping in the middle of a sentence)
- poor judgement (e.g. with money)
Explain physiological cleavage of the amyloid precursor protein
Amyloid precursor protein = physiological role and present in membranes of neuronal cells
- Gets cleaved by alpha-secretase
- Gets cleaved again by gamma-secretase
- products that are produced are being removed
Explain the pathophysiological cleavaage of the Amyloid precursor protein according to the amyloid hypothesis of the cause of alzheimers
- Amyloid precursor protein is cleaved by beta-secretase (instead of alpha-secretase)
- produced a larger cleavage product than alpha-secretase
- Product is cleaved by gamma-secretase
- produces ß-amyloid protein (Aß)
- can’t be removed and forms toxic aggregates
Summarise the Amyloid Hypothesis in the aetiology of Alzheimers
One theory of explaining alzheimers
- instead of alpha-secretase, ß-secretase cleaves the Amyloid precursor protein
- gamma-secretin cleaves into ß-amyloid protein that forms toxic aggregates in neurons (can’t be removed)
- Causing neurodegeneration
What is Tau protein?
What is its function?
Soluble protein present in axons
Important for assembly & stability of microtubules
Explain the Tau Hypothesis in regards to Alzheimer
Way of explaining the Neurodegeneration
- Tau protein gets hyperphosphorilated
- turns soluble protein into insoluble comopound
- self-aggregates to form neurofibrillary tangles
- Aggregates are neurotoxic
- Also results in Microtubule Instability
- turns soluble protein into insoluble comopound
–> Axonal loss and Neurodegeneration
Explain the inflammation hypothesis for the development of Alzheimers
In Alzheimers: Microglia (which are normally specialised immune cells in the brain) get hyperactive leading to
- increased release of inflammatory mediators and cytotoxic proteins
- increased phagocytosis
- decreased levels of neurorotective protiens
Name the different theories of the development of Alzheimers disease and explain how they relate to each other
- ß-Amyloid hypothesis
- Tau Hypothesis
- Iflammation Hypothesis
–> Possibly a combination of all three (e.g. 1+2 together cause 3) but not known and well understood yet
What are the two drug classes used in Alzheimer treatment?
Management of symptoms
- Antincholinesterases
- NMDA receptor blocker
Explain the reasonale behind the effective treatments of Alzheimers disease
Noone really knows why they work but overall:
- it is a symptomatic approach (don’t stop progression of disease)
- Normally enhance Ach or modulate NMDA receptor
Where is the NMDA receptor located?
What is the neurotransmitter binding to it?
Located in the CNS
–> Get activated by Glutamate
Name different Anticholinesterases used in the treatment of Alzheimers and their characteristics
-
Donepezil
- Reversible cholinesterase inhibitor
- Long plasma half-life (only taken OD)
-
Rivastigmine
- Pseudo-reversible AChE & BChE (Butyrylcholinesterase) inhibitor
- inhibits both forms of cholinesterases which leads to more side effects
- 8 hour half-life
- Reformulated as transdermal patch
- Pseudo-reversible AChE & BChE (Butyrylcholinesterase) inhibitor
-
Galantamine
- Reversible cholinesterase inhibitor
- 7-8 hour half-life
- Additional: direct a7 nAChR agonist (subtype that is found in CNS)
What are the effects of drug treatment in Alzheimers?
- Has an immediate effect on memory loss, which is very effective at first (but only for a maximum of the first two years)
Which drugs can be used in mild to moderate forms of Alzheimers treatment?
- Donepezil (often preferred one) but also
- Rivastigme
- Galantamine
–> All the Anicholinesterases
