Amyloid plaques are aggregates of misfolded proteins that form in the spaces between nerve cells. These abnormally configured proteins are thought to play a central role in Alzheimer's disease. The amyloid plaques first develop in the areas of the brain concerned with memory and other cognitive functions.
The amyloid hypothesis
Amyloid plaques form when pieces of protein called beta-amyloid aggregate. The beta-amyloid is produced when a much larger protein referred to as the amyloid precurosr protein (APP) is broken down. APP is composed of 771 amino acids and is cleaved by two enzymes to produce beta-amyloid. The large protein is first cut by beta secretase and then by gamma secretase, producing beta-amyloid pieces that may be made up of 38, 40 or 42 amino acids. The beta-amyloid composed of 42 amino acids is chemically “stickier” than the other lengths and therefore is more likely to form plaques. Research has shown that three genetic abnormalities that are associated with early stage Alzheimer’s disease each change the function of gamma secretase in a way that leads to an increased production of beta-amyloid 42.
How beta-amyloid causes toxic damage to nerve cells is not quite clear, but some research suggests that it may split into fragments and release free radicals, which then attack neurons. Another theory is that the beta-amyloid forms tiny holes in neuronal membranes, which leads to an unregulated influx of calcium that can cause neuronal death. Regardless of the exact pathological process through which beta-amyloid causes neuronal damage, the result is that neurons die.
Plaques then form that are made up of a mixture of these degenerating neurons and the beta-amyloid aggregates. These plaques cannot be broken down and removed by the body, so they gradually accumulate in the brain. The accumulation of this amyloid leads to amyloidosis, which is thought to contribute to a number of neurodegenerative diseases.
Amyloid plaques form one of the two defining features of Alzheimer’s disease, the other being neurofibrillary tangles. Beta-amyloid is also thought to be responsible for the formation of these tangles, which again damage neurons and cause the symptoms of dementia. Technically, a person may present with all of the characteristics of Alzheimer’s disease but if a brain biopsy or positron emission tomography does not reveal the presence of amyloid plaques or neurofibrillary tangles, a diagnosis of Alzheimer’s disease will not be made.
The treatment currently available to treat Alzheimer’s disease only addresses symptoms rather than the underlying cause, but research that focuses on the amyloid hypothesis and improves understanding of this protein’s role in the disease is hoped to lead to the development of new treatments that may be able to delay or stop disease progression.
Several treatments that either remove beta-amyloid or interfere with its production from APP are currently being designed and tested. Approaches to preventing beta-amyloid production involve targeting the beta-secretase and gamma-secretase that are required to make it from APP. Some research in animal models has shown preventing the action of these two enzymes to be successful and several drugs based on this mechanism have reached Phase III trails. Another approach that has been investigated is preventing the aggregation of beta-amyloid in order to prevent plaque formation. Several drug candidates have been identified that seem to prevent this protein clumping and these agents are now due to be tested in animal models of Alzheimer’s disease.
Another approach currently being investigated is the removal of the amyloid plaques or proteins that form in the brain. In 2014, researchers from Stanford University published the ground breaking results of a study that investigated the function of microglia in amyloid plaque formation. Microglia are resident macrophages in the central nervous system that are responsible for removing bacteria, viruses and abnormal deposits from the brain in order to maintain its function. The researchers found that nerve cells die when the microglia stop working (which tends to occur as people age) and a protein referred to as EP2 stops the microglia from functioning efficiently. By blocking this protein, the team found the normal function of microglia was restored, which allowed them to clean up the sticky amyloid plaques which accumulate in Alzheimer’s disease. When a drug was used to block EP2 in mice, the researchers found that memory loss was reversed in the animals as well as many other symptoms of the disease.
Overall, laboratory research has shown promising evidence that it may be possible to prevent the formation of amyloid plaques or to boost the brain’s immune response to clear the deposits once they have formed. Results from trials in humans over the next five years should indicate whether a cure for Alzheimer’s disease is indeed a realistic possibility in the future.