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5BBM0218 Physiology and Pharmacology of CNS > L15: Alzheimer's Disease > Flashcards

L15: Alzheimer's Disease Flashcards

1
Q

What is the typical age of onset for Alzheimer’s disease?

A

after 60 years old

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2
Q

What percentage of dementia cases does Alzheimer’s disease account for?

A

65% of dementia cases

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3
Q

What are the two drug classes used to treat Alzheimer’s disease?

A
  1. Anti-cholinesterases: These drugs inhibit the acetylcholinesterase, which breaks down ACh (NT involved in memory & cognitive function)
  2. NMDA receptor antagonists: These drugs block the N-methyl-D-aspartate (NMDA) receptors, which are involved in learning and memory processes
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4
Q

What are some common symptoms of Alzheimer’s disease?

A

Amnesia: Loss of memory.
Aphasia: Impaired language and communication abilities.
Apraxia: Problems with carrying out voluntary movements.
Agnosia: Difficulty recognizing sensory stimuli, such as faces.
Mood and behavioural disturbances: Changes in mood and behaviour may also be observed in individuals with Alzheimer’s disease

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5
Q

What are senile plaques?

A

Senile plaques are aggregations of beta-amyloid protein on neuronal cell surfaces

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6
Q

How are senile plaques formed?

A
  • formed due to a disorder in the processing of amyloid precursor protein
  • large aggregations can block cell surfaces and prevent endocytosis
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7
Q

What is the genetic linkage to senile plaques, and what environmental factors increase the risk for Alzheimer’s disease?

A
  • more than 50 mutations in the APP gene can lead to increased beta-amyloid or a stickier peptide.
  • elevated risk associated with high BP & elevated cholesterol
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8
Q

What are neurofibrillary tangles?

A

result from hyperphosphorylation of the protein tau.

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9
Q

What are neurofibrillary tangles, and how do they occur?

A
  • Neurofibrillary tangles result from hyperphosphorylation of the protein tau.
    (- Tau normally binds to microtubules and contributes to their stability)
  • Hyperphosphorylation causes tau to detach from microtubules, leading to their collapse
  • Disorganization of the cytoskeleton and cell death occur
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10
Q

What are neurofibrillary tangles, and how do they occur?

A
  • Neurofibrillary tangles result from hyperphosphorylation of the protein tau.
    (- Tau normally binds to microtubules and contributes to their stability)
  • Hyperphosphorylation causes tau to detach from microtubules, leading to their collapse
  • Disorganization of the cytoskeleton and cell death occur
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11
Q

2 main pathological features of AD

A
  • presence of these amyloid plaques
  • & neurofibrillary tangles

(required for a pathological diagnosis)

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12
Q

What happens in the early phase of AD?

A
  • Neurons in the nucleus basalis Meynert degenerate, which is the origin of major projections to the neocortex.
  • Cholinergic neurons are lost, leading to a reduction in choline acetyltransferase (ChaT) enzyme.
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13
Q

What areas are most affected by the cholinergic system in Alzheimer’s disease?

A

-the cortex
- hippocampus
- basal forebrain
- ventral striatum.

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14
Q

Which specific region of cholinergic neurons is most affected in Alzheimer’s disease?

A
  • Cholinergic neurons located in the basal forebrain region are most affected in AD
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15
Q

What is the cognitive role of acetylcholine (ACh) in Alzheimer’s disease?

A
  • ACh plays a significant cognitive role in AD
  • formation of beta-amyloid plaques alters synaptic ACh neurotransmission, contributing to cognitive impairment
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16
Q

What happens to the remaining cholinergic neurons in Alzheimer’s disease?

A
  • remaining cholinergic neurons in AD show decreased ChaT activity.
  • leads to diminished output from the hippocampus and neocortex, which are the two main sites involved in cognition and memory
17
Q

Which region of the brain has the most affected cholinergic neurons in Alzheimer’s disease?

A
  • increase the concentration ACh in the brain
  • can delay cognitive impairment by 1-3 years in 20% of patients, but do not alter disease progression
18
Q

Name some cholinesterase inhibitors used to treat Alzheimer’s disease

A

Donepezil: A selective reversible inhibitor of AchE
Galantamine: A reversible competitive inhibitor with agonist activity at pre-synaptic nicotinic receptors
Rivastigmine: A slow reversible inhibitor that inhibits both AchE and BchE

19
Q

Describe the side effects of Donepezil, Galantamine and Rivastigmine

A

Donepezil: GI upset, loss of appetite, difficulty sleeping, and muscle cramps.
Galantamine: It may cause GI side effects.
Rivastigmine: vomiting, diminished appetite, and weight loss.

20
Q

What is the weak excitotoxicity hypothesis in Alzheimer’s disease?

A
  • suggests that beta-amyloid plaques increase the vulnerability of neurons to glutamate, leading to excitotoxicity
  • beta-amyloid interacts with NMDA receptors, enhancing excitotoxicity
21
Q

How can M1 agonists enhance cholinergic transmission in Alzheimer’s disease?

A
  • M1 agonists can enhance cholinergic transmission, improve cholinergic deficiency, cognitive function & reduce tau and beta-amyloid pathologies in AD
  • Activation of M1 receptors ↓ tau hyperphosphorylation and ↑ alpha secretase, which helps prevent beta-amyloid accumulation
22
Q

How does the neuronal nicotinic acetylcholine receptor A4b2 protect against Alzheimer’s disease, and what happens when there is a reduction in the A4 subunit?

A
  • A4b2 (type of neuronal nicotinic ACh receptor) has high nicotine binding and is sensitive to upregulation by nicotine
  • reduction in A4 subunit by 80% in AD impairs protective effect of A4b2.
  • B2 null mutation mice with reduced A4b2 experience early-onset neurodegeneration.
23
Q

How does the neuronal nicotinic acetylcholine receptor A4b2 protect against Alzheimer’s disease, and what happens when there is a reduction in the A4 subunit?

A
  • A4b2 (type of neuronal nicotinic ACh receptor) has high nicotine binding and is sensitive to upregulation by nicotine
  • reduction in A4 subunit by 80% in AD impairs protective effect of A4b2.
  • B2 null mutation mice with reduced A4b2 experience early-onset neurodegeneration.
24
Q

What is the role of the A7 homomeric neuronal nicotinic acetylcholine receptor in Alzheimer’s disease?

A
  • A7 homomeric receptor has brief open time, desensitizes rapidly & impacts activation of second messenger systems
  • High levels of beta-amyloid impair response of the A7 receptor
  • A7 and A4b2 receptors protect against toxicity of beta-amyloid plaques
  • but beta-amyloid preferentially kills A7 receptors over A4b2
25
Q

What is the mechanism of action of memantine, a drug used to treat Alzheimer’s disease?

A
  • memantine = uncompetitive NMDA receptor antagonist
  • at low clinical concentrations - promotes synaptic plasticity, preserve/enhance memory, & improve cognition in animal models of AD
  • It inhibits weak NMDA receptor-dependent excitotoxicity, (which is hypothesized to contribute to progressive neuronal loss in AD)
  • may also inhibit beta-amyloid production & reduce beta-amyloid plaque toxicity
26
Q

Why is memantine preferred over ketamine for the treatment of Alzheimer’s disease?

A
  • because it selectively blocks low tonic levels of glutamate, preserving glutamate response required for normal behavioural functioning, cognition & memory.
  • ketamine is a non-competitive NMDA receptor antagonist that can have broader effects on glutamate signalling ∴ lead to undesirable side effect
27
Q

What are some adjunct therapies used in Alzheimer’s disease, and what are their effects?

A
  • Donepezil and memantine are adjunct therapies used in AD
  • 5-HT3 receptor antagonists are also used
  • have relatively modest effects but are well-tolerated
    (some side effects: dizziness, confusion, and headache)
28
Q

How many drugs are available for the treatment of Alzheimer’s disease, and what are their names?

A

only 4:
donepezil
galantamine
rivastigmine
and memantine

5BBM0218 Physiology and Pharmacology of CNS (17 decks)

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