Gamma-Secretase Activating Protein Suggested As Alzheimer's Drug Target

A study identified gamma-secretase activating protein (GSAP) as a therapeutic target for prevention or treatment of Alzheimer's disease.

Gamma-secretase is a multi-subunit protease complex, itself an integral membrane protein, that cleaves single-pass transmembrane proteins at residues within the transmembrane domain. The most well-known substrate of gamma-secretase is amyloid precursor protein, a large integral membrane protein that, when cleaved by both gamma-and beta-secretase, produces a short 39-42 amino acid peptide called amyloid-beta whose abnormally folded fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients. Gamma-secretase is also critical in the related processing of the Notch protein.

The study, published in the September 2, 2010, online edition of the journal Nature, points the way for development of drugs to prevent gamma-secretase from producing amyloid-beta while not interfering with its interaction with Notch, which is essential for normal biological functions.

Investigators at The Rockefeller University (New York, NY, USA) reported the discovery of a novel gamma-secretase activating protein (GSAP) that drastically and selectively increased amyloid-beta production through a mechanism involving its interactions with both gamma-secretase and its substrate, the amyloid precursor protein carboxy-terminal fragment (APP-CTF). GSAP did not interact with Notch, nor did it affect its cleavage.

Recombinant GSAP stimulated amyloid-beta production in vitro. Reducing GSAP concentrations in cell lines decreased amyloid-beta concentrations. Knockdown of GSAP in a mouse model of Alzheimer's disease reduced levels of amyloid-beta and plaque development. The anticancer drug imatinib, which had been found previously to inhibit amyloid-beta formation without affecting Notch cleavage, was shown to achieve its amyloid-beta-lowering effect by preventing GSAP interaction with the gamma-secretase substrate, APP-CTF.

"Millions of people suffer from Alzheimer's disease, and treatment options are limited,” said senior author Dr. Paul Greengard, professor of molecular and cellular neuroscience at The Rockefeller University. "Existing drugs may mask symptoms for a time but do nothing to stop the relentless downward progression of Alzheimer's. What are needed are safe and effective medications that will halt the cause of the underlying disease. It is our hope that this gamma-secretase activating protein will greatly add to the creation of safe and effective Alzheimer's treatments.”

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