Selective Modulation of Gamma-Secretase May Reverse Alzheimer's Disease

A new generation of drugs for treatment of Alzheimer's disease (AD) will prevent formation of amyloid-beta peptide-42 (A-beta42), the accumulation of which is considered by many researchers to be the cause of the disease.

In most forms of AD, abnormally large quantities of the long amyloid peptide-42 are formed due to the inappropriate action of the cleavage enzyme gamma-secretase. 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 (APP), 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.

Investigators at the Ecole Polytechnique Fédérale de Lausanne (Switzerland) studied a particularly aggressive early-onset type of familial Alzheimer’s disease that appears as early as thirty years of age and leaves patients with a life expectancy of only a few years.

They reported in the August 2, 2013, online edition of the journal Nature Communications that this syndrome was caused by mutations in the transmembrane domain of APP that affected both gamma- and epsilon-cleavage sites, by raising the A-beta42/40 ratio. The longer A-beta42 peptide is the form that aggregates into toxic amyloid plaques.

New drugs now under development change the location where gamma secretase cleaves the APP protein, thus producing amyloid peptide 38 instead of 42, which is shorter and does not aggregate into plaques.

"Scientists have been trying to target gamma secretase to treat Alzheimer's for over a decade," said senior author Dr. Patrick Fraering, professor of neurosciences at the Ecole Polytechnique Fédérale de Lausanne. "Our work suggests that next-generation molecules, by modulating rather than inhibiting the enzyme, could have few, if any, side-effects. It is tremendously encouraging."

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