Alzheimer's disease

Question 1

Describe some risk factors of AD?

Answer 1

Age is biggest risk factors.

Also small contribution from genetics: APP, PSEN (mutation in the genes increase the risk of early-onset AD) ApoE ( mutation here increases likelihood of late-stage AD).

Question 2

What are some symptoms of AD?

Answer 2

Memory loss
Disorientation/ confusion
Language problems
Personality changes
Poor judgement

Question 3

Describe how amyloid precursor protein is dealt with physiologically?

Answer 3

Amyloid precursor protein (APP) cleaved by alpha secretase
sAPP alpha released and a C83 fragment remains
C83 digested by gamma secretase
Products removed

Question 4

What is the amyloid hypothesis?

Answer 4

APP cleaved by beta secretase rather than alpha
sAPP beta released and a C99 fragment remains
C99 digested by gamma secretase releasing beta amyloid
beta amyloid forms toxic aggregates

Question 5

What are tau proteins?

Answer 5

Soluble protein present in axons

Important for assembly & stability of microtubules

Question 6

What is the tau hypothesis?

Answer 6

In AD you get phosphorylation of Tau proteins
Hyperphosphorylated tau is insoluble and self-aggregates to form neurofibrillary tangles
These are neurotoxic
This also results in microtubule instability

Question 7

Why are anticholinesterases used to treat AD?

Answer 7

Increasing acetylcholine levels correlates with improved symptoms of AD.

Question 8

Give 3 examples of anticholinesterases used in treating AD

Answer 8

Donepezil
Reversible cholinesterase inhibitor.
Long plasma half-life

Rivastigmine
Pseudo-reversible AChE & BChE inhibitor but due to affecting butryl has more side effects
8 hour half-life
Reformulated as transdermal patch

Galantamine
Reversible cholinesterase inhibitor
7-8 hour half-life
Mediates some action as an alpha 7 nicotinic receptor agonist (found in CNS)

Question 9

Why are NMDA receptors targets in AD?

Answer 9

In late-stage neurodegenration you get a big upregulation of excitatory synapses and loss of GABA transmission.

Question 10

Give an example of an NMDA receptor blocker used to treat AD?

Answer 10

Memantine
Use-dependent non-competitive NMDA receptor blocker with low channel affinity- more effective if receptor is firing more thus only used in late stage.
Only licensed for moderate-severe AD
Long plasma half-life