Alzheimer's disease
- a progressive neurodegenerative disease that leads to symptoms of dementia.
- pathophysiology of this disease is quite complex and not entirely understood.
Content:
2. Drug
3. Future of Alzheimer’s disease treatments
4. Reference
1. 3 hypotheses that try to explain the cause of Alzheimer’s
a. Cholinergic hypothesis
the loss of central cholinergic neurons and ensuing deficiency of acetylcholine, a neurotransmitter involved in memory and learning.
b. Amyloid hypothesis
caused by accumulation of abnormally folded beta-amyloid proteins.
Beta-amyloid:
- a metabolic waste product present in the fluid between brain cells
- clumps together to form amyloid plaques, which are thought to induce neuroinflammation and disrupt communication between neurons.
c. Tau hypothesis
abnormal aggregation of Tau proteins that leads to the formation of tangles within nerve cells in the brain.
When Tau dissociates, the microtubule assembly becomes compromised
- disrupting the neuron's transport system
- malfunctions in biochemical communication between neurons.
Microtubules: transport of nutrients and information molecules throughout the neuron.
2. Drug
Current therapeutic options are limited to drugs that provide only mild symptomatic benefit.
Two classes: (1) cholinesterase inhibitors and (2) NMDA receptor antagonist
a. Cholinesterase inhibitors
- alleviate the symptoms of the disease
- work by inhibiting cholinesterase enzymes from breaking down acetylcholine
- increasing both the level and duration of action of acetylcholine
- Drug:
- Donepezil
- Rivastigmine
- significant inhibition of both acetylcholinesterase and butyrylcholinesterase
- Galantamine
Side effect:
- nausea
- vomiting
- diarrhea
- slow heartbeat
- lack of appetite
- substantial weight loss
Normal conditions: cholinergic neurons in the brain
- synthesize acetylcholine from acetyl coenzyme A (acetyl CoA) and choline
- in a reaction catalyzed by an enzyme choline acetyltransferase (CAT)
- Upon arrival of neuronal impulse, synthesized acetylcholine is released into the synaptic cleft
- interacts with acetylcholine receptors located on the postsynaptic neurons
- acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) break down acetylcholine into acetate and choline
- terminating stimulating signals
b. NMDA receptor antagonist
NMDA receptors
- belong to the family of ionotropic glutamate receptors
- mediatemost of the excitatory synaptic transmission in the brain.
- important in learning and memory formation.
Beta-amyloid proteins that accumulate in the brain
- cause abnormal rise in extrasynaptic glutamate levels by
- inhibiting glutamate uptake
- triggering glutamate release from glial cells
When glutamate levels become abnormally elevated,
- overstimulation of NMDA receptors
- excessive influx of calcium
- cell to rapture and die.
- Drug: Memantine
- works by blocking NMDA receptors and thus limiting calcium influx into the neuron
Side effects associated with Memantine
- diarrhea
- headache
- insomnia
3. Future of Alzheimer’s disease treatments
a. Beta-amyloid
Researchers are investigating agents that may prevent beta-amyloid fragments from clumping into plaques by targeting two enzymes, β-secretase and γ-secretase, which sequentially cut the amyloid precursor protein to generate the pathological beta-amyloid peptides.
In another approach, researchers have also been testing antibodies that bind to bet-amyloid and enhance its clearance from the brain.
b. Tau protein
Tau protein is the main component of tangles.Just like with beta-amyloid, antibodies capable of binding and clearing pathological Tau proteins are currently being developed and tested.
Another area of extensive research involves compounds that prevent tau aggregation or dissolve existing aggregates, as well as compounds that inhibit microtubule disassembly.
4. Reference
https://youtu.be/euzRPrvrwj0
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