Alzheimer's disease Flashcards
Main risk factor for alzheimer’s disease?
age
Early onset Alzheimer’s disease (hereditary) is caused by mutations in genes such as?
APP, PSEN, ApoE
Clinical symptoms of Alzheimer’s disease include?
Memory loss Disorientation/ confusion Language problems (stopping in the middle of a conversation) Personality changes (fearful, anxious) Poor judgement
State the name of one of the main hypothesis explaining the mechanism behind Alzheimer’s disease.
Amyloid hypothesis
In the physiological processing of Amyloid precursor protein (APP), which two cleavage proteins are involved? What happens?
alpha-secretase
gamma-secretase
They both cleave APP => 3 separate products to be removed
In the pathophysiological processing of APP (amyloid hypothesis), which two cleavage proteins are involved? What happens?
beta-secretase
gamma-secretase
- The beta-secretase cleaves at a different site on APP.
- One of the products released is beta-amyloid protein.
- beta-amyloid protein forms toxic aggregates around neurons and other cells => neurodegeneration
Where and how are tau proteins normally present in the neuron? What are they important for?
Soluble protein present in axons
Important for assembly & stability of microtubules
Another important hypothesis explaining Alzheimers’s disease?
Tau hypothesis
*Note that the Tau and Amyloid hypothesis are thought to occur together (so not one or the other)
Describe the Tau hypothesis
- Tau becomes hyperphosphorylated
- This form of tau is insoluble => they aggregate inside the cell and form neurofibrillary tangles
- These tangles are neurotoxic and result in microtubule instability
=> neurodegeneration
Describe the inflammation hypothesis
Microglial cells (macrophages of the CNS):
- release more inflammatory mediators & cytotoxic proteins
- increase phagocytosis
- decrease levels of neuroprotective proteins
What are the currently licensed drugs for the treatment of Alzheimer’s disease? Used for what kind of AD?
Anticholinesterases (for mild-moderate AD):
- Donepezil
- Rivastigmine
- Galantamine
NMDA receptor blocker (for moderate-severe AD):
- Memantine
Donepezil
- type of inhibitor
- half-life
Reversible acetylcholinesterase inhibitor.
Long plasma half-life
Rivastigmine
- type of inhibitor
- plasma half-life
- administration
Pseudo-reversible cholinesterase inhibitor
8 hour half-life
Transdermal patch
Galantamine
- type of inhibitor
- plasma half-life
- additional action
Reversible cholinesterase inhibitor
7-8 hour half-life
alpha7 nAChR agonist
Memantine
- type of NMDA receptor blocker
- plasma half-life
Use-dependent non-competitive NMDA receptor blocker with low channel affinity
Long plasma half-life
