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New drugs to find the right target to fight Alzheimer's disease
Date:8/2/2013

understanding of the mechanism involved has been lacking. But with this work, the EPFL researchers were able to shed some more light on it by determining how the drug compounds affect gamma secretase and its cutting activity.

In most forms of Alzheimer's, abnormally large quantities of the long amyloid peptide 42 named like that because it contains 42 amino acids are formed. The drug compounds change the location where gamma secretase cuts the APP protein, thus producing amyloid peptide 38 instead of 42, which is shorter and does not aggregate into neurotoxic plaques.

Compared to previous therapeutic efforts, this is considerable progress. In 2010, Phase III clinical trials had to be abandoned, because the compound being tested inhibited gamma-secretase's function across the board, meaning that the enzyme was also deactivated in essential cellular differentiation processes, resulting to side-effects like in gastrointestinal bleeding and skin cancer.

"Scientists have been trying to target gamma secretase to treat Alzheimer's for over a decade," explains Patrick Fraering, senior author on the study and Merck Serono Chair of Neurosciences at EPFL. "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."

New insights into hereditary forms of the disease

During their investigation, the scientists also identified possible causes behind some hereditary forms of Alzheimer's disease. Early-onset Alzheimer's can appear as early as thirty years of age, with a life expectancy of only a few years. In vitro experiments and numerical simulations show that in early-onset patients, mutations in the APP protein gene modify the way by which APP is cut by the gamma-secretase enzyme. This results in overproduction of amyloid peptide 42, which then aggregates into amyloid plaques.

This research illuminates much
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Contact: Patrick Fraering
patrick.fraering@epfl.ch
41-795-938-785
Ecole Polytechnique Fdrale de Lausanne
Source:Eurekalert

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