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.
