Structure and Function - Week 9 Alzheimer's

Question 1

Describe the cholinergic hypothesis of Alzheimer’s disease (3)

Answer 1

Changes in cholinergic neuron markers and receptors have been reported over the years.

Basal forebrain cholinergic nuclei one area to degenerate in Alzheimer’s.

Hypothesis is also based on the established role of acetylcholine in cognition and memory.

Question 2

Describe the mechanism by which cholinesterase inhibitor work (3)

Answer 2

AChEIs inhibits the hydrolysis of acetylcholine by acetylcholinesterase

Increases the amount of acetylcholine available in the synaptic cleft

Rivastigmine also inhibits butylcholinesterase (dual mechanism of action)

Question 3

Describe clinical effects of cholinesterase inhibitor (3)

Answer 3

Modest benefits in symptoms – slowing cognitive decline but not disease modifying.

More chance of benefit if used in mild to moderate stages of Alzheimer’s.

May be less effective in other forms of dementia (e.g. vascular dementia on left).

Question 4

Describe glutamate hypothesis (3)

Answer 4

Excess glutamate or alterations in glutamate receptors linked to Alzheimer’s disease.

Excess glutamate spills over from synapse – activates extrasynaptic NMDA receptors (pro-apoptotic pathways and/or excitotoxicity).

Question 5

Describe the mechanism by which memantine work (3)

Answer 5

Voltage-dependent uncompetitive NMDA-receptor antagonist. Competes with Mg2+ and therefore limits Na+/Ca2+ influx.

Physiological function of NMDA-Rs unaffected due to uncompetitive nature and voltage-dependence – aims to prevent excitotoxicity.

Question 6

Describe clinical effects of memantine (3)

Answer 6

Used for moderate to severe Alzheimer’s, or for people who can’t take cholinesterase inhibitors
Mixed reports of efficacy at the late stages of disease.

Question 7

Describe amyloid hypothesis (3)

Answer 7

Amyloid-beta precursor protein (APP) cleaved by secretase enzymes.

When cleaved by beta and gamma-secretases, neurotoxic amyloid beta peptides produced  aggregation  main component of plaques

Question 8

Describe the mechanism by which anti-amyloid drugs work (3)

Answer 8

Targeting of various stages e.g. inhibiting secretases, preventing aggregation, or antibodies against distinct phases.