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2010 New Investigator Research Grant (NIRG)

Trans-suppression of Abeta amyloidogenesis in cellular and nematode models

Giuseppe Di Fede, M.D., Ph.D.
Fondazione IRCCS Istituto Neurologico Carlo Besta
Milan, Italy

Alzheimer's disease is characterized by brain accumulations of the protein fragment beta-amyloid. This fragment, which is produced from a "parent" molecule called amyloid precursor protein, may hinder cell-to-cell communication in the brain and cause brain cell death. A rare inherited form of Alzheimer's, which often affects people at a relatively young age, is caused by mutations in APP that lead to beta-amyloid production.

Giuseppe Di Fede, M.D., Ph.D., and colleagues have found a mutated site on the APP molecule that may cause early-onset Alzheimer's. This mutation only affects people who inherit two copies of abnormal APP from their parents. For such people, the mutation tends to 1) foster the production of beta-amyloid from APP and 2) promote the accumulation of beta-amyloid molecules into toxic clumps. In people with only one copy of the gene, interactions between normal beta-amyloid and the beta-amyloid produced by the mutant APP prevent harmful clumping—and prevent the development of Alzheimer's disease.

For this proposed study, the investigators will search for biological mechanisms underlying their APP variant's ability to promote harmful amyloid clumping. They also plan to study how interactions between mutant beta-amyloid and normal beta-amyloid prevent such clumping in people with only one copy of the variant. Their work will be conducted with cultured cells and with roundworms engineered to possess one or two copies of the mutant APP.

Dr. Di Fede's effort could shed new light on the genetic underpinnings of inherited, early-onset Alzheimer's disease. It could also lead to more targeted disease therapies and prevention strategies.

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