The Beta Amyloid

The amyloid plaque found in Alzheimer's disease (AD) are made of beta amyloid, a protein fragment snipped from a larger protein called amyloid precursor protein. These fragments clump together and are mixed with other molecules, neurons, and non-nerve cells. In AD, plaques develop in the hippocampus, a structure deep in the brain that helps to encode memories, and in other areas of the cerebral cortex that are used in thinking and making decisions. 

Beta amyloid plays a central role in the development of AD. Its insights let us understand the effects of cholesterol and apolipoprotein E on AD. The early-onset familial AD that occurs between the ages of 30 and 60 has also been demonstrated to result from mutations of the genes involved in the production of beta amyloid. For this reason, beta amyloid is an important target in the development of new drugs against AD.

From APP to Beta Amyloid (Ab)

The amyloid precursor protein (APP) appears to be important in helping neurons grow and survive. APP may help damaged neurons repair themselves and may help parts of neurons grow after brain injury. After it is made, APP sticks through the neuron's membrane, partly inside and partly outside the cell.

The beta amyloid (Ab) is generated by two enzymes which cut APP at two different positions:  b-secretase cuts APP at a position outside the cell and  g-secretase cuts APP at a position inside the cell membrane. The resulting Ab peptide contains about 40 amino acids.

The g-secretase lacks sequence specificity. Its cleavage site may shift slightly, depending on the molecular structure of the enzyme and its environment. As a result, the length of Ab ranges from 39 to 43 amino acids. It has been found that the longer one is more likely to form plaques than the shorter one. Researchers usually use two Ab peptides to compare their toxicities: Ab with 40 amino acids (represented as Ab₄₀) and Ab with 42 amino acids (represented as Ab₄₂). Ab₄₂ is more toxic than Ab₄₀.

The Toxicity of Ab

Individual Ab peptides can be cleared away by degradative enzymes such as  insulin-degrading enzyme, neprilysin, and plasmin. After they aggregate to form plagues, they are difficult to be removed. The plagues may induce inflammatory responses, creating oxygen free radicals. In addition, they may promote the formation of neurofibrillary tangles, resulting in cell death (more info).

In a normal brain, Ab₄₀ is produced at higher level than Ab₄₂. However, the amyloid plaque in Alzheimer's disease is composed primarily of Ab₄₂. Experiments have also shown that Ab₄₂ aggregates more rapidly than Ab₄₀, consistent with other observations that Ab₄₂ is more toxic than Ab₄₀.

AD Genetics and Ab

Four genes have been conclusively shown to affect the development of Alzheimer's disease: the APP gene on chromosome 21, the PS1 gene on chromosome 14, the PS2 gene on chromosome 1, and the apoE gene on chromosome 19. Mutations of APP, PS1 and PS2 genes are linked to the rare early-onset form of familial AD. Many people with Down's syndrome also develop AD-like dementia by the age of 40. They have three copies of chromosome 21 (where the APP gene is located), instead of two for normal people.

The APP gene encodes the precursor protein to beta amyloid. One more copy of the APP gene in people with Down's syndrome should make more precursor proteins, thereby producing more Ab peptides. Mutations of the APP gene in the early-onset AD either increase the total level of Ab peptides or favor the production of Ab₄₂ (more info). Both cases increase the chance of forming amyloid plaques.

PS1 and PS2 genes encode presenilin 1 and presenilin 2, respectively. They are the components of the g-secretase, which cleaves APP to generate Ab. Their mutations favor the production of Ab₄₂.

The apoE gene enclodes apolipoprotein E (apoE) which helps carry cholesterol in the blood. The effects of apoE and cholesterol on beta amyloid are discussed in a separate page.

Reference:

National Institute on Aging, USA