Dementia science

Question 1

how do acetylcholinesterase inhibitors work

Answer 1

inhibits acetylcholinesterase to keep acetylcholine in the synapse for longer

Question 2

what is the benefit to using galantamine over other AChEIs

Answer 2

also inhibits BuChE - non-specific but can break down ACh

Question 3

what are NMDA antagonists and how do they work

Answer 3

memantine - Glutamate toxicity is proposed to play a role in neuronal cell death - as cells die glutamate is realised
This can cause excitotoxicity and further cell death - this is stopped by memantine

Question 4

what are the main roles of acetylcholine in the CNS

Answer 4

• widely distributed
• Cholinergic interneurons in the striatum involved in movement` control
• Also roles in arousal and reward pathways (nicotine addiction)

Question 5

which pathways in the brain use ACh

Answer 5

• Nucleus basalis projects to cortex
• Septal nuclei project to hippocampus - memory!
• Brainstem to thalamus - motor control

Question 6

how does ACh cause dementia

Answer 6

• loss of cholinergic neurons in basal forebrain and hippocampus
• ACh decreased
• atrophy of hippocampus and enlarged ventricles
• formation of beta-amyloid plaques and intra-neuronal neurofibrillary tangles
• starts in hippocampus and spreads

Question 7

what is the beta-amyloid protein

Answer 7

peptide produced from amyloid precursor protein (APP) - cleaved by a (sAPP) and y (b-amyloid) secretases

Question 8

what is APP

Answer 8

amyloid precursor protein - large transmembrane glycoprotein
- in neuronal and non cells
- transcriptional regulator
- growth factor function
- synaptic transmission

Question 9

what happens if APP is cleaved by b and y secretases

Answer 9

AB40 and 42 formed - found in plaques - AB42 is the worst

Question 10

which mutations can cause increased AB42 formation

Answer 10

APP mutations
presenilin mutations can increase y-secretase activity

Question 11

how does Amyloid B form the plaques associated with AD

Answer 11

combine to oligomer which combine to fibrils and then plaques

Question 12

what are AD plaques made of

Answer 12

fibrils
cell parts
astrocytes
microglia
apolipoproteins

Question 13

what are neurofibrillary tangles

Answer 13

formed from hyperphosphorylated tau that aggregates to form paired helical filaments - causes microtubules to depolymerise and causes neuronal cell death

Question 14

what is the normal action of tau

Answer 14

normally stabilises microtubules

Question 15

which mutations are responsible for early onset AD

Answer 15

• trisomy 21 - down syndrome (APP on chromosome 21 - 3 copies)
• APP mutations - favours AB42
• presenilin - component of y secretase - favours AB42
• tau - increased phosphorylation

Question 16

which mutations are responsible for late onset AD

Answer 16

ApoE gene variants
- lipid binding lipoprotein
- involved in lipid transport and found in plaques
- ApoE4 increased risk
- ApoE2 decreased risk

Question 17

what must acetylcholinesterase inhibitors do

Answer 17

cross BBB

Question 18

what is the SAR for donepezil

Answer 18

• carbonyl required
• dimethoxy substitution optimal - para most important
• 5 C ring essential
• CH2 bridging optimal
• N in 6C ring essential
• substitution with EDG is good but unsub is preferred

Question 19

how does donepezil work

Answer 19

AChE selective inhibitor and reversible

Question 20

SAR for carbamates natural product

Answer 20

• carbamate essential - reacts with catalytic triad
• Amine important for activity - pka 7 50% ionised in body
• benzene hydrophobic good leaving group

Question 21

how does rivastigmine work

Answer 21

pseudo-irreversible, enzyme inhibition lasts for longer then the drug is in plasma

Question 22

rivastigmine SAR

Answer 22

same as carbamate SAR
- carbamate essential - catalytic triad
- benzene ring makes good leaving group
- amine