Alzheimer's disease

Question 1

Name the theories of alzheimer’s pathophysiology

Answer 1

Beta amyloid
Tau protein
Inflammation

Question 2

Recall the normal physiological metabolism of APP

Answer 2

1. Amyloid precursor protein (APP) cleaved by alpha-secretase
2. sAPPalpha released from cleaving and C83 fragment remains on membrane
3. C83 is then digested by gamma-secretase

Products from both cleavages are removed

Question 3

Recall the theorised pathophysiological metabolism of APP

Answer 3

Pathophysiological processing
1. APP cleaved by beta-secretase (theres more Beta secretase than the physiological alpha version)
2. sAPPbeta released (shorter than sAPPalpha) - C99 fragment remains (bigger fragment than C83)
3. C99 is digested by gamma-secretase, releasing beta-amyloid (Abeta) protein
Abeta forms toxic aggregates (plaques) which surround neurones and cause cell death

Question 4

What is tau protein?

Answer 4

Tau proteins are Soluble proteins surrounding microtubules. Microtubules are involved in transporting things from cell body to axon nerve terminal
Tau proteins are Important for assembly & stability of microtubules

Question 5

Recall the tau protein theory of alzheimers pathophysiology

Answer 5

Hyperphosphorylation of tau makes it insoluble

Tau proteins autoaggregate to form neurotoxic neurofibrillary tangles leading to cell death and microtubule instability

Question 6

Recall the inflammatory theory of alzheimers pathophysiology

Answer 6

Inappropriate activation of microglia increases inflammatory mediators, cytotoxic proteins and phagocytosis + decreases neuroprotective protein expression

Question 7

Recall 5 clinical symptoms of Alzheimers disease

Answer 7

Memory loss – especially recently acquired information
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

Jake MD loves parkinson’s

Question 8

Recall three genetic associations with alzheimers disease and which of these associate to early-onset and late-onset disease

Answer 8

Mutations in:
APP (EOD)
PSEN (EOD)
ApoE (LOD)

Question 9

Recall the 2 classes of drugs currently approved for use in Alzheimer’s

Answer 9

Anticholinesterases

NMDA receptor antagonists

Question 10

Recall 3 examples of anti-cholinesterases

Answer 10

Donepezil
Rivastigmine
Galantamine

Question 11

Name an example of an NMDA receptor antagonist

Answer 11

Memantine:

use dependent and non-competitive NMDA receptor antagonist

Question 12

Differnetiate the indications for anticholinesterase vs NMDAr antagonist use in Alzheimer’s

Answer 12

Anticholinesterase = mild-moderate disease

NMDAR antagonist = severe disease

Question 13

Which of the anti-cholinesterase drugs is the gold standard and why?

Answer 13

Donepezil

Long half life

Question 14

Recall the general MOA of donepezil

Answer 14

Reversible cholinesterase inhibitor

Question 15

How does rivastigmine’s MOA differ from donepezil, and what is the consequence of this?

Answer 15

1. Is pseudo-reversible

2. Also antagonises butyrylcholinesterases as well as AChesterases, so has additional side effects

Question 16

Recall the MOA of galantamine, how this differs from doneprezil and the consequences of this

Answer 16

1. Reversibly inhibits ACh esterase
2. Also agonises the alpha 7 subunit of nAChRs ( a type of NEURONAL nicotinic AChR) –> decreased symptoms of Alzheimer’s

Question 17

Describe why memantine is only indicated in severe disease

Answer 17

It is use-dependent as neurodegeneration causes increased activation of NMDA receptors by glutamate.

Question 18

Recall 3 classes of drug that were “treatment failures” for Alzheimer’s

Answer 18

Beta amyloid antibodies
Tau protein inhibitors
Gamma secretase inhibitors