Before we go there, let’s look at these plaques and tangles. First of all, we could have development
of plaques. Those plaques happen, the beta amyloid plaques happen between different neurons,
so outside of the neuron between neurons and perhaps interrupt signaling. The second component
are these neurofibrillary tangles which occur inside the neurons and block the passage of signaling
molecules and nutrients to and from the nucleus. Let’s take a closer look at the beta amyloid plaques.
We’ll deal with those first to look at where they are derived from. We can see in the first figure here
there is what we call amyloid precursor protein. It’s a normal protein in the cell membrane.
For some reason, it gets clipped and released. These pieces of beta amyloid are released.
The beta amyloid piece of this protein that’s released is particularly sticky. So, it will associate
with other pieces that are sticky and cause a beta amyloid plaque, so association of different pieces
of the same kind of protein. These occur between neurons, again outside of the cell.
They interrupt communication between cells especially at the synapses. When the cells stop
communicating with each other, they stop getting signals that’s worth living on. So, the immune response
comes in and starts clearing those cells. So, we see degeneration of those neurons.
The cells actually undergo apoptosis and are removed which is why we see a decrease in brain size.
I’ll show you an image of that shortly. The second component where these neurofibrillary tangles,
if you can say that mouthful in front of a camera, good on you, neurofibrillary tangles result from
abnormalities in proteins within the cell. First of all, recall that there are microtubules inside of every cell.
They’re part of the cytoskeletal network. Microtubules in particular are about transporting things
around in the cells. This pink and yellow molecule here is a microtubule. It may extend the length
of a whole neuron as we transport things from the nucleus, perhaps neurotransmitters and such,
all the way down to the signaling end or to the extreme regions of the cell. These rails, so to speak
are held stably in line. Let’s imagine they’re railroad tracks. Perhaps, we need to spike them down
so that they don’t move when the trains come by. They are stabilized by a protein called tau.
So, the tau protein in Alzheimer's comes out in a mutated form or begins to become mutated.
So, the tau protein no longer acts to stake down the tracks which then disrupts the continuity
of the tracks so that these molecular motors and transport proteins can’t run along them anymore.
These tangles prevent passageway of all the nutrients and goods along the length of the neuron.
Consequently, the neuron is not signaling in the way that it should and it will be degraded.
That is what leads us to the development of reduced brain size at the end of the progression
of Alzheimer's disease. Again, I mentioned there’s a characteristic spread of Alzheimer's.
As we watch Alzheimer's progress in individuals, we first see that learning and memory is lost.
We see excessive loss of learning and memory associated with damage in the anterior temporal lobe.
Then it will generally progress towards degeneration in thinking and planning future events.
That is a consequence of damage that we see in the frontal lobe. Then it moves more to the posterior
region of the temporal lobe and starts affecting speech and communication. As the disease progresses,
you can see the development of the beta amyloid plaques and neurofibrillary tangles progress
throughout the brain. As it spreads to other regions, for example the parietal lobe, individuals start
losing their sense of location and their surrounding environment. Again, this is a fairly characteristic
spread of Alzheimer's disease. It’s not exactly the way it happens all the time. So, you may witness
different progressions in different individuals. Here is a great image showing the sort of scope
of neuronal death, right? A regular brain on the left-hand side and over on the right-hand side,
we see a brain that has been affected by Alzheimer's. There’s much reduced mater shrinkage
in the cerebral cortex as well as expanded ventricle. This is not really a good outcome
but there’s serious evidence of actual degradation of neurons, right? They’ve been destroyed
because of the beta amyloid plaques or the neurofibrillary tangles and a combination of both.
How do we treat Alzheimer's disease? One of the things that we think about in communication
between neurons, if you were to name a neurotransmitter that you know exists in the brain,
what would it be? Right, acetylcholine. Acetylcholine where we see reduction of the number of neurons
and thus the reduction of signaling between neurons and the reduction of acetylcholine.
So, that’s one of the characteristics or one of the features that ends up in Alzheimer’s
displaying the way it does. One of the most frequent treatments is the use of cholinesterase inhibitors.
The idea here is that we prevent the destruction of acetylcholine so that it remains present
in the synapse for longer and has more potential to signal the neuron downstream. It’s fairly effective
at treating Alzheimer's for a certain amount of time. Of course, the disease is progressive so eventually,
we’re going to go down the path of degeneration anyway. A fairly new advent, although a not new drug
is the use of a drug called memantine sold under the name of Namenda, which actually has been around
for quite some time since the late 60s. It was initially made to treat diabetes. It turns out that
it’s fairly effective at treating later stages of Alzheimer's disease also. It is indeed a cholinesterase
inhibitor also but it affects the NMDA receptor, too. What it does is antagonizes that NMDA receptor
to block glutamate receptors. So, we see that glutamate doesn’t have as much of an effect.
It’s suggested that the reason that it does this is in some Alzheimer's patients, we may see
an excess of glutamate which overstimulates. When a glutamate is there overstimulating receptors
then we see loss in memory and disassociation there. So, by blocking the NMDA receptors,
we decrease the action of glutamate and thus decrease the progression of the disease.
So, a drug that’s been around for a long time that has resurfaced as a potential treatment.
It’s fairly successful in later stages of Alzheimer's although not as successful in the earlier stages
where we’re just seeing increased forgetfulness.