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Understanding the Amyloid Connection

Alzheimer’s can be compared to coronary artery disease (atherosclerosis), in which plaques composed of cholesterol form in blood vessels and block blood flow to the heart. In Alzheimer’s, plaques made up of a brain protein called beta amyloid (or a-beta) form in the spaces between nerve cells, blocking the normal flow of communication between cells and impairing brain function.

Just as there is “good” and “bad” cholesterol in our arteries, there is “good” and “bad” amyloid in the brain. Both types are formed when a larger parent protein called amyloid precursor protein (APP) is snipped by little molecular “scissors” known as secretases. The bad type, called beta amyloid or a-beta, is formed when APP gets snipped sequentially by two of these scissors (beta secretase and gamma secretase). As beta amyloid levels rise, gooey clumps of protein -- amyloid plaques -- start to accumulate, gumming up nerve-cell communications and eventually leading to cell death.

When a different set of scissors (alpha secretase) snips the amyloid precursor protein, the result is good amyloid, which does not form plaques and is not toxic to nerve cells. These two pathways seem to work in opposition: the more non-toxic amyloid that is produced by the good pathway, the less poisonous beta amyloid builds up in the brain.

By understanding these fundamental processes, scientists can now develop or identify drugs that might interrupt the bad pathway or step up activity of the good pathway in order to slow down the production of beta amyloid.

But the rate at which beta amyloid is produced is just one piece of the Alzheimer’s puzzle. How fast it clumps up and how quickly it is cleared from the brain are also critical, and these represent additional therapeutic leads. For example, so-called Alzheimer’s vaccines harness the body’s inherent immune-system defenses to attack and destroy amyloid plaques and/or speed up clearance of amyloid before it accumulates into plaques. Other investigational therapies – including two being studied in clinical trials at Farber – interrupt the clumping of beta amyloid into plaques.

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