In this lecture we’re gonna cover the pharmacology of drugs used in treatment of Alzheimer's disease,
so lets get right into it.
Alzheimer’s disease is a progressive neurodegenerative disease that leads to symptoms of dementia.
The pathophysiology of this disease is quite complex and not entirely understood.
However, there are currently few different hypotheses that try to explain the cause of
Alzheimer’s.
The most popular ones include: (1) Cholinergic hypothesis, which states that a possible cause
of Alzheimer’s is the loss of central cholinergic neurons and ensuing deficiency of acetylcholine,
a neurotransmitter involved in memory and learning.
(2) Amyloid hypothesis, which states that Alzheimer's may be caused by accumulation
of abnormally folded beta-amyloid proteins.
Beta-amyloid is a metabolic waste product present in the fluid between brain cells.
In Alzheimer’s disease, beta-amyloid clumps together to form amyloid plaques, which are
thought to induce neuroinflammation and disrupt communication between neurons.
Lastly, at (3) we have Tau hypothesis, which proposes that Alzheimer’s may result from
abnormal aggregation of Tau proteins that leads to the formation of tangles within nerve
cells in the brain.
In a healthy brain, the Tau protein helps to lengthen and support microtubule structure.
Microtubules play crucial role in transport of nutrients and information molecules throughout
the neuron.
So when Tau dissociates, the microtubule assembly becomes compromised thereby disrupting the
neuron's transport system leading to malfunctions in biochemical communication between neurons.
Now, when it comes to treatment of Alzheimer’s disease, current therapeutic options are limited
to drugs that provide only mild symptomatic benefit.
We can divide those drugs into two classes: (1) cholinesterase inhibitors and (2) NMDA receptor antagonist.
So, let’s talk about these for a minute starting with cholinesterase inhibitors.
Under 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 where it interacts with acetylcholine receptors located on the postsynaptic neurons.
Shortly after, two enzymes, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) break
down acetylcholine into acetate and choline, thus terminating stimulating signals.
Now, since Alzheimer’s has been linked to a deficiency of acetylcholine in the brain,
cholinesterase inhibitors were introduced to alleviate the symptoms of the disease.
As their name suggests, cholinesterase inhibitors work simply by inhibiting cholinesterase enzymes
from breaking down acetylcholine, thereby increasing both the level and duration of
action of acetylcholine.
The three commonly prescribed cholinesterase inhibitors are Donepezil, Rivastigmine, and
Galantamine.
It’s important to note here that out of the three, Rivastigmine is the only one that
shows significant inhibition of both acetylcholinesterase and butyrylcholinesterase.
When it comes to side effects, they can range from mild, such as nausea, vomiting, and diarrhea,
to potentially serious, such as slow heartbeat, lack of appetite and substantial weight loss.
Now, let’s move onto our next drug class that is NMDA receptor antagonist.
So, NMDA receptors belong to the family of ionotropic glutamate receptors, which mediate
most of the excitatory synaptic transmission in the brain.
They are thought to play an important role in learning and memory formation.
Research suggests that beta-amyloid proteins that accumulate in the brain of Alzheimer’s
patients may cause abnormal rise in extrasynaptic glutamate levels by inhibiting glutamate uptake
or triggering glutamate release from glial cells.
Now, as you may know, the binding of glutamate to the NMDA receptor results in an influx
of extracellular calcium, which controls membrane excitability and synaptic transmission.
So when glutamate levels become abnormally elevated, overstimulation of NMDA receptors
can result, leading to excessive influx of calcium, ultimately causing cell to rapture
and die.
To address this potential problem, scientists developed NMDA receptor antagonist called
Memantine, which works by blocking NMDA receptors and thus limiting calcium influx into the
neuron.
Common side effects associated with Memantine include diarrhea, headache, and insomnia.
Now before we end I wanted to briefly discuss the future of Alzheimer’s disease treatments.
So, currently available drugs that we discussed so far provide temporary relief of symptoms,
however, they do not stop or slow down the underlying neurodegenerative process.
This is why new experimental drugs are now being developed to target the root causes
of the disease.
One of the major promising targets for future drugs is 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.
The second major target of future therapies is Tau protein, 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.
Now, despite all the optimism surrounding a large pipeline of drugs in clinical trials,
so far the field of Alzheimer’s research has been filled with disappointments as many
promising drugs have failed to show significant improvement in slowing down the progression
of the disease.
However, there’s always a lot we can learn from failure, and with every failed trial,
we find out more about the disease and what might work to stop it.
And with that I wanted to thank you for watching, I hope you enjoyed this video and as always
stay tuned for more.