UF identifies potential new pathway to halt Alzheimer’s progression

University of Florida neuroscientists have validated a potential pathway to halt the progression of Alzheimer’s disease, a debilitating neurodegenerative disorder that affects millions of Americans and is the most common cause of dementia. The investigators made the finding while studying the toxicity of products that result from abnormal protein processing in the brain.

A wide body of genetic, pathologic and modeling literature all have shown how protein pieces called amyloid beta —known as Abeta — play a pivotal role in triggering Alzheimer’s disease. There are many forms of Abeta produced in the brain, but scientists recognize the accumulation of one form in particular — Abeta 42, which is composed of 42 amino acids — as key in promoting Alzheimer’s disease. Abeta peptides, or chains of amino acids, are produced by an enzyme called gamma-secretase.

One class of compounds previously developed to treat Alzheimer’s disease is known as gamma-secretase modulators, which have been shown to lower levels of Abeta 42 but raise levels of shorter Abeta peptides. These compounds do not completely inhibit the enzyme, however, but instead shift the enzyme’s activity. Some studies have suggested that the increase of shorter peptides could be harmful.

But in recent findings, a team of neuroscientists at the Evelyn F. and William L. McKnight Brain Institute of the University of Florida report that the short Abeta peptides were not toxic in two animal models — a mouse and a fruit fly — and in fact were protective from the toxic effects of Abeta 42, said MBI director Todd E. Golde, M.D., Ph.D.

The findings hold the potential for a drug therapy to stop Alzheimer’s progression to be tested in humans. Medications currently in use target the symptoms but not the disease progression of Alzheimer’s. More than 5 million Americans are currently living with the disease.

Previously developed drug therapies aimed at thwarting abnormal Abeta accumulation have not been successful, and it’s believed that some of the most promising ones have yet to make it to trial because of concerns over safety in humans.

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