Features | Partner Sites | Information | LinkXpress
Sign In
JIB
GLOBETECH PUBLISHING
GLOBETECH PUBLISHING

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

By BiotechDaily International staff writers
Posted on 22 Aug 2013
Image: Enzymes act on the APP (Amyloid precursor protein) and cut it into fragments of protein, one of which is called beta-amyloid, which is crucial in the formation of senile plaques in Alzheimer's disease (Photo courtesy of Wikimedia Commons).
Image: Enzymes act on the APP (Amyloid precursor protein) and cut it into fragments of protein, one of which is called beta-amyloid, which is crucial in the formation of senile plaques in Alzheimer's disease (Photo courtesy of Wikimedia Commons).
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."

Related Links:

Ecole Polytechnique Fédérale de Lausanne



comments powered by Disqus

Channels

Drug Discovery

view channel
Image: Synthetic ion transporters can induce apoptosis by facilitating chloride anion transport into cells (Photo courtesy of the University of Texas, Austin).

Experimental Drug Kills Cancer Cells by Interfering with Their Ion Transport Mechanism

An experimental anticancer drug induces cells to enter a molecular pathway leading to apoptosis by skewing their ion transport systems to greatly favor the influx of chloride anions. To promote development... Read more

Therapeutics

view channel
Image: Liver cells regenerated in mice treated with a new drug (right) compared with a control group (center) after partial liver removal. Healthy liver cells are shown at left (Photo courtesy of Marshall et al, 2014, the Journal of Experimental Medicine).

New Drug Triggers Liver Regeneration After Surgery

Investigators have revealed that an innovative complement inhibitor decreases complement-mediated liver cell death, and actually stimulates postsurgery liver regrowth in mice. Liver cancer often results... Read more

Business

view channel

Partnership Established to Decode Bowel Disease

23andMe (Mountain View, CA,USA), a personal genetics company, is collaborating with Pfizer, Inc. (New York, NY, USA), in which the companies will seek to enroll 10,000 people with inflammatory bowel disease (IBD) in a research project designed to explore the genetic factors associated with the onset, progression, severity,... Read more
 
Copyright © 2000-2014 Globetech Media. All rights reserved.