Transgenic Mouse Offers New Clues To Alzheimer's Disease

November 18, 1996

Mice engineered with a human gene linked to an inherited form of Alzheimer's Disease (AD) produce more of the main ingredient of a substance called amyloid found in the brains of AD patients, according to Johns Hopkins researchers.

"We found that mice with this particular mutant gene produced 50 percent more A-beta42(43), the long form of the A-beta amyloid peptide," says David Borchelt, Ph.D., an assistant Hopkins professor of pathology.

A-beta peptides are part of the protein known as amyloid-precursor protein or APP. Working with researchers at the National Cancer Institute, Borchelt, Gopal Thinakaran, Ph.D., and the Mayo Clinic's Chris Eckman, Ph.D., developed genetically engineered mice and a line of cultured cells that carry parts of a human gene for APP and human genes for another AD-related protein, presenilin-1.

The new finding, scheduled to be presented at the Society for Neuroscience's annual meeting, suggests a cascade of events in the development of AD that could be targeted for drug treatment. The study was funded by the National Institutes of Health, the National Institute on Aging and the Adler Foundation.

Researchers created two types of mice: one with a normal presenilin-1 gene and one with a mutated presenilin-1 gene. Mutations in presenilin-1 and a related protein, presenilin-2, are linked to FAD, which strikes patients unusually early in life.

"We think presenilin-1 somehow regulates the process that chops up APP and produces A-beta peptides," says Borchelt.

"This is an exciting discovery because it gives us a tool to explore the mechanisms by which cells produce amyloid peptides," says Thinakaran.

Borchelt and his colleagues plan to monitor the mice, now seven months old, for characteristics and symptoms of AD, and for the links between presenilin-1 and APP.

--JHMI--

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Johns Hopkins Medicine

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