Pharmacology CNS Dementia Flashcards
Describe the pathological findings of AD:
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
Describe the atrophy in cerebral cortex and hippocampus in AD:
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
Describe the pre-clinical brain features of AD:
Changes in hippocampus (memory)- frontal and prefrontal cortex (cognition)
Describe the clinical brain features of AD:
Spreads to the rest of the brain
What is B-amyloid and how is it produced?
Is a 36-43 a.a peptide produced from amyloid precursor protein (APP) by the action of proteases called secretases
What is APP?
A large transmembrane glycoprotein (770 a.a long)
What is the function of APP?
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)
Name the different secretases that can cleave APP:
alpha
Beta
Gamma
Describe a-secretase involvement in APP:
Cleaves extracellular (90%)
a-secretase produces soluble APP (sAPP) and C terminal fragment A (CTFa)
Can then be cleaved by y-secretase
Describe B-secretase involvement in APP:
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
Describe AB40 and AB42:
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
What is presenilin and what occurs if there is mutations in this?
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
Describe the cleavage of AB:
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
Name the components of the AB plaque:
BA fibrils
Apolipoproteins
Dystrophic neurites (damaged parts of cells)
Astrocytes
Microglia (attracted to limit debris but then becomes part of it)
Describe the underlying theory of disease progression in AD:
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
What is the consequence of plaque associated proteins (apolipoproteins) being incorporated into fibril to produce an extracellular plaque?
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
What are neurofibrillary tangles?
Formed from a protein called TAU that a has become hyperphosphorylated
AB can influence formation of the TAU protein
What does TAU do normally without AD?
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
What does TAU do in AD?
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
Name the Ach pathways in the brain involved in early pre-clinal AD:
Nucleus basalis (cell body) projects to cortex (synapses)
Septal nuclei (cell body) projects to hippocampus (synapses)
Name the Ach pathways in the brain less involved in AD:
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)
Describe the neurochemical changes of Ach in relation to AD:
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
What is early onset AD?
Less than 60 years old
Accounts for around 5% of AD
What genetic factor can predispose to early AD and why?
Trisomy 21 (Downs syndrome)
As 3 copies of chromosome 21 leads to increased APP and BA
APP is on chromosome 1
Name the key proteins that mutations can occur in that causes early onset AD:
APP
Presenilin (PSEN1 and PSEN2)
TAU
How can APP mutations cause early onset AD?
Causes APP cleavage favouring AB42 production
How can TAU mutations cause early onset AD?
Increase in phosphorylation
What is late onset dementia?
Occurs after the age of 60 years old
Majority of cases
Describe ApoE:
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
Describe different alleles of the ApoE gene which can cause AD:
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
What is the reason of using AchEi in AD?
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
What are the extra effects of galantamine?
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
What are the effects of AchEi?
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
How does memantine work?
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
Name future developments of AD drugs:
Anti-amyloid therapies
Anti-aggregration therapy
How could anti-amyloid therapies work?
Inhibition or modulation of B and y secretase
How could anti-aggregation therapy work?
Decrease in the formation of BA plaques
Decrease or inhibition of phosphorylation of TAU
