Alzheimer's Disease and Amyloid Plaques

Adapted from Purdue University/Fenil Patel

As discussed in a previous post (found here), one of the most alarming pathological features of Alzheimer’s disease is the presence of large clumps of the amyloid-beta peptide known as amyloid-beta plaques. Since these plaques are intimately connected to the pathophysiology of Alzheimer’s disease, they are often referenced as a potential target for treating or even curing the disease.

These clumps build up between neurons (like plaque on one's teeth), impairing the connection between two brain cells. This impairment in communication between neurons can eventually, or rather, ultimately, lead to neuronal death, contributing to the progressive neurodegenerative symptoms of Alzheimer’s disease.

So why do these plaques form?

This is a question that might be more easily answered if it is first understood how these plaques form.

Sticking out of the cell membrane of a brain cell is a protein called the amyloid precursor protein (APP). Normally, an enzyme called alpha-secretase snips off a fragment of APP that projects out of the cell membrane. After this, another enzyme, gamma-secretase, snips off another chunk of APP. Part of the separated fragments of APP is released from the neuron, while another part of APP is sent inward to the nucleus of the neuron. All of these fragments, when snipped by the proper enzymes, aid in the plasticity of the brain, learning, memory, and neuronal survival. It is also important to note that these fragments are soluble, meaning they can easily dissolve when released by a neuron.

In a brain afflicted with Alzheimer’s, however, it is not alpha-secretase that snips a fragment of the amyloid precursor protein – instead, it is an enzyme called beta-secretase. This enzyme snips off a smaller fragment than its counterpart. This, of course, causes problems for gamma-secretase, who then snips a differently sized fragment than normal. The result is the insoluble fragment, amyloid-beta 40/42 peptide, which will then be released from the neuron.

After leaving the neuron, amyloid-beta 40/42 interacts with a protein that has been shown to transport cholesterol in the brain, apolipoprotein E (APOE). The product of this interaction is the aggregation of those amyloid-beta oligomers. This aggregation leads to the formation of amyloid-beta plaques.

The presence of amyloid-beta then affects the ability of the neuron to uptake glutamate, one of the main excitatory neurotransmitters crucial for learning and memory. This essentially means that this neurotransmitter cannot be recycled as normal, and so it accumulates in the synapse and leads to neuronal hyperactivity. More information on this can be found in our previous post on Alzheimer’s disease.

Understanding the dynamics of Alzheimer’s disease presents researchers with many different avenues to explore for potential cures. For example, amyloid-beta 40/42's interaction with APOE has led researchers to focus on APOE's function – which will be discussed in a future post. With all this being said, there is much more to Alzheimer’s disease that will be mentioned in the following articles.