L15: Alzheimer's Disease Flashcards
What is the typical age of onset for Alzheimer’s disease?
after 60 years old
What percentage of dementia cases does Alzheimer’s disease account for?
65% of dementia cases
What are the two drug classes used to treat Alzheimer’s disease?
- Anti-cholinesterases: These drugs inhibit the acetylcholinesterase, which breaks down ACh (NT involved in memory & cognitive function)
- NMDA receptor antagonists: These drugs block the N-methyl-D-aspartate (NMDA) receptors, which are involved in learning and memory processes
What are some common symptoms of Alzheimer’s disease?
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
What are senile plaques?
Senile plaques are aggregations of beta-amyloid protein on neuronal cell surfaces
How are senile plaques formed?
- formed due to a disorder in the processing of amyloid precursor protein
- large aggregations can block cell surfaces and prevent endocytosis
What is the genetic linkage to senile plaques, and what environmental factors increase the risk for Alzheimer’s disease?
- 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
What are neurofibrillary tangles?
result from hyperphosphorylation of the protein tau.
What are neurofibrillary tangles, and how do they occur?
- 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
What are neurofibrillary tangles, and how do they occur?
- 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
2 main pathological features of AD
- presence of these amyloid plaques
- & neurofibrillary tangles
(required for a pathological diagnosis)
What happens in the early phase of AD?
- 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.
What areas are most affected by the cholinergic system in Alzheimer’s disease?
-the cortex
- hippocampus
- basal forebrain
- ventral striatum.
Which specific region of cholinergic neurons is most affected in Alzheimer’s disease?
- Cholinergic neurons located in the basal forebrain region are most affected in AD
What is the cognitive role of acetylcholine (ACh) in Alzheimer’s disease?
- ACh plays a significant cognitive role in AD
- formation of beta-amyloid plaques alters synaptic ACh neurotransmission, contributing to cognitive impairment
What happens to the remaining cholinergic neurons in Alzheimer’s disease?
- 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
Which region of the brain has the most affected cholinergic neurons in Alzheimer’s disease?
- 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
Name some cholinesterase inhibitors used to treat Alzheimer’s disease
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
Describe the side effects of Donepezil, Galantamine and Rivastigmine
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.
What is the weak excitotoxicity hypothesis in Alzheimer’s disease?
- suggests that beta-amyloid plaques increase the vulnerability of neurons to glutamate, leading to excitotoxicity
- beta-amyloid interacts with NMDA receptors, enhancing excitotoxicity
How can M1 agonists enhance cholinergic transmission in Alzheimer’s disease?
- 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
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?
- 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.
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?
- 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.
What is the role of the A7 homomeric neuronal nicotinic acetylcholine receptor in Alzheimer’s disease?
- 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
