Pharmacology CNS Dementia

Question 1

Describe the pathological findings of AD:

Answer 1

Atrophy in cerebral cortex and hippocampus
Microscopic features:
Plaques (extracellular) containing B-amyloid peptide
Intra-neuronal neurofibrillary tangles (intercellular) composed primarily of hyperphosphorylated TAU protein
Functional losses in cholinergic, GABAergic and monoaminergic transmitter systems

Question 2

Describe the atrophy in cerebral cortex and hippocampus in AD:

Answer 2

Neuronal and synaptic losses- widened sulci and larger gaps between gyri, loss of SA so loss of grey matter
15-20% decrease in hippocampus volume in mild disease
Ventricles enlarged

Question 2

Describe the pre-clinical brain features of AD:

Answer 2

Changes in hippocampus (memory)- frontal and prefrontal cortex (cognition)

Question 3

Describe the clinical brain features of AD:

Answer 3

Spreads to the rest of the brain

Question 4

What is B-amyloid and how is it produced?

Answer 4

Is a 36-43 a.a peptide produced from amyloid precursor protein (APP) by the action of proteases called secretases

Question 5

What is APP?

Answer 5

A large transmembrane glycoprotein (770 a.a long)

Question 6

What is the function of APP?

Answer 6

Not fully known
Found in many cells, neuronal and non-neuronal
Cleavage part of the physiological mechanisms:
-transcriptional regulation
-GF regulation (inner part)
-role in synaptic transmission (outer part)

Question 7

Name the different secretases that can cleave APP:

Answer 7

alpha
Beta
Gamma

Question 8

Describe a-secretase involvement in APP:

Answer 8

Cleaves extracellular (90%)
a-secretase produces soluble APP (sAPP) and C terminal fragment A (CTFa)
Can then be cleaved by y-secretase

Question 9

Describe B-secretase involvement in APP:

Answer 9

Cleaves within the transmembrane domain- within the membrane (10%)
Cleavage by B and Y secretase leads to production of B-amyloid (AB)- toxic and CTFB
AB40 and AB42 are mainly produced, 40=a.a long

Question 10

Describe AB40 and AB42:

Answer 10

Both found in plaques
AB40 is most abundant (80-90%)
AB42 (10-20%) is most insoluble and most amyloidogenic- most likely to form amyloid plaques
Mutations in APP increase proportion of AB42

Question 11

What is presenilin and what occurs if there is mutations in this?

Answer 11

Catalytic part of the y-secretase complex- the catalytic part
Mutations in presenilin which increase y-secretase activity so increases AB42 production
PSEN1 is most common mutation, found columbian families with early onset AD

Question 12

Describe the cleavage of AB:

Answer 12

AB after cleaved (monomer)
Into an oligomer- as has hydrophobic regions it will associate with other monomers
Into fibril- associated with other oligomers
Form the plaques

Question 13

Name the components of the AB plaque:

Answer 13

BA fibrils
Apolipoproteins
Dystrophic neurites (damaged parts of cells)
Astrocytes
Microglia (attracted to limit debris but then becomes part of it)

Question 14

Describe the underlying theory of disease progression in AD:

Answer 14

Soluble AB oligomers- even before form the plaques are disruptive to neurons
This affects NMDA dependent Ca2+ influx signalling
Synaptic dysfunction
Disrupted long term potentiation (LTP)
Neuronal cell death

Question 15

What is the consequence of plaque associated proteins (apolipoproteins) being incorporated into fibril to produce an extracellular plaque?

Answer 15

Direct cytotoxic effect
Inflammatory response (microglial activation, cytokine release) as this becomes chronic the inflammatory process becomes detrimental to neuronal tissue leads to mitochondrial damage and oxidative stress to neuronal cell death

Question 16

What are neurofibrillary tangles?

Answer 16

Formed from a protein called TAU that a has become hyperphosphorylated
AB can influence formation of the TAU protein

Question 17

What does TAU do normally without AD?

Answer 17

TAU stabilises MTs- important within neuronal cell as run the length of axon, important for axonal transport from one end of the neurone to the other
When TAU is phosphorylated it causes MT depolymerisation (detachment) so causes normal process

Question 18

What does TAU do in AD?

Answer 18

The TAU is no longer attached to MT and aggregate to form paired helical filaments (PHF) into neurofibrillary tangles because the TAU protein can no longer associate with MTs, MTs depolymerise so leads to loss of axonal transport to leads to neuronal cell death

Question 19

Name the Ach pathways in the brain involved in early pre-clinal AD:

Answer 19

Nucleus basalis (cell body) projects to cortex (synapses)
Septal nuclei (cell body) projects to hippocampus (synapses)

Question 20

Name the Ach pathways in the brain less involved in AD:

Answer 20

Widely distributed- unlike NMDA and GABA, Ach is in discreet pathways
Brain stem projects to the thalamus (motor control)
Cholingeric interneurons in the stratum involved in control of movement
Also roles in arousal (wakefulness) and reward pathways (nicotine addiction)

Question 21

Describe the neurochemical changes of Ach in relation to AD:

Answer 21

Post mortem brain tissue demonstrates selective loss of cholinergic neurons in basal forebrain (nucleus basalis projecting to cortex) and hippocampus (from septal nucleus)- involved in cognition, learning, memory
Decrease choline acetyl transferase activity (50-90% decrease) and other markers (AchE) in hippocampus and cortex
Decrease nicotinic receptor density in the cortex
Ach content decreased

Question 22

What is early onset AD?

Answer 22

Less than 60 years old
Accounts for around 5% of AD

Question 23

What genetic factor can predispose to early AD and why?

Answer 23

Trisomy 21 (Downs syndrome)
As 3 copies of chromosome 21 leads to increased APP and BA
APP is on chromosome 1

Question 24

Name the key proteins that mutations can occur in that causes early onset AD:

Answer 24

APP
Presenilin (PSEN1 and PSEN2)
TAU

Question 25

How can APP mutations cause early onset AD?

Answer 25

Causes APP cleavage favouring AB42 production

Question 26

How can TAU mutations cause early onset AD?

Answer 26

Increase in phosphorylation

Question 27

What is late onset dementia?

Answer 27

Occurs after the age of 60 years old
Majority of cases

Question 28

Describe ApoE:

Answer 28

4 variants of ApoE gene 1-4 (2,3,4 most common)
Lipid binding lipoprotein
Involved in transport of lipids
2 versions of allele, one from mother, one from father
Apolipoprotein is found in the plaques which has a role in plaque clearance

Question 29

Describe different alleles of the ApoE gene which can cause AD:

Answer 29

ApoE4 expression is strongly linked with the risk of developing AD
ApoE4 variant is less effective at clearing AB
Carrying 2 ApoE4 alleles gives the highest risk, ApoE2 decreases risk

Question 30

What is the reason of using AchEi in AD?

Answer 30

In pathophysiology of AD, we get a selective loss of cholinergic neurons, so using AchEi, increase amount of Ach and increase activity at cholingeric synapses to make up for neuronal loss

Question 31

What are the extra effects of galantamine?

Answer 31

Blocks BuchE which also has activity at Ach to break it down, so might boost action further
It is also a modulator at nicotinic receptors, nicotinic receptors on post synaptic membrane (M or N type) or pre-synaptic membrane (N)
It is a positive allosteric modulator so enhances the activity of these receptors so increases downstream actions of nicotinic receptor on presynaptic receptor, they modulate +ve feedback, when Ach binds, causes more Ach to be released

Question 32

What are the effects of AchEi?

Answer 32

Improves cognitive function (small but measurable) in mild to moderate AD
Relies on some intact cholinergic neurons to synthesise Ach, hence they are more beneficial in early stages of the disease

Question 33

How does memantine work?

Answer 33

A non-competitive NMDAr antagonist
By inhibiting the NMDAr this will limit excess glutamate toxicity (excitotoxicity)
Excitotoxicity is proposed to play a role in neuronal cell death in AD:
-neuronal function deteriorates and cells die, glutamate is released causing 2º cell death
Cognitive improvement in moderate- severe AD

Question 34

Name future developments of AD drugs:

Answer 34

Anti-amyloid therapies
Anti-aggregration therapy

Question 35

How could anti-amyloid therapies work?

Answer 35

Inhibition or modulation of B and y secretase

Question 36

How could anti-aggregation therapy work?

Answer 36

Decrease in the formation of BA plaques
Decrease or inhibition of phosphorylation of TAU