Beta Amyloid: Causes of Alzheimer’s Disease

Learn about Amyloid Beta, a protein implicated as a cause of Alzheimer’s disease, & how research into Amyloid Beta has opened possible treatment options. At The Emergent Universe, an online interactive science museum about emergence.

The Puzzle of Beta Amyloid

All of our bodies produce the protein Beta Amyloid. In those with Alzheimer’s, Beta Amyloid, which normally has no preferred structure, folds in a way that promotes aggregation and is thought to initiate a cascade of pathologic events. If this is correct, eliminating Beta Amyloid would shut down Alzheimer’s.

Can we stop Beta Amyloid production?

Beta Amyloidis produced from a larger protein called the Alzheimer’s Precursor Protein (APP). In the first step, an enzyme called b-secretase (“beta-secretase”) cuts off one end of the APP protein.

Treatment Target: Can we eliminate Beta Amyloid by eliminating beta-secretase?

Genetically modified mice that don’t have b-secretase don’t produce Beta Amyloid and don’t develop Alzheimer’s. They also live viably without Beta Amyloid, although their learning is slightly impaired.

The first pharmaceuticals designed to inhibit beta-secretase, and thus Beta Amyloid, in humans were too large to cross the blood-brain barrier. Researchers have now developed smaller beta-secretase inhibitors, one of which began clinical trials in 2007.

Can we stop Beta Amyloid production?

After its cleavage by beta-secretase, the remainder of APP is cut by a second enzyme called gama-secretase to form Beta Amyloid. This second cut can be made at different places, creating forms of Beta Amyloid that differ in length from Beta Amyloid 40, which is a chain 40 units long, to Beta Amyloid 42, which is 42 units long.

Treatment Target: Can we eliminate Beta Amyloid by targeting gamma-secretase?

The design of safe gamma-secretase inhibitors has been hampered by the fact that gamma-secretase has other important duties beyond simply cleaving APP. Successful gamma-secretase inhibitors must therefore only modify this enzyme’s APP-cleaving function. As of 2008, numerous candidate drugs are under development and in clinical trials; however, one of the earliest of such drugs has already failed to show the expected efficacy against Alzheimer’s in clinical trials.

What’s aging got to do with it?