Cure Alzheimer’s disease by modulating

Aug 29, 2014 | | Say something

Cure Alzheimer’s disease by modulating ; gamma-secretase

The future looks good for drugs designed to combat Alzheimer’s disease. Learn about new knowledge that has the potential to keep Alzheimer’s disease in check.

EPFL scientists have revealed how two classes of drug compounds currently in clinical trials work to combat Alzheimer’s disease. Their research suggests that these compounds target the peptides that cause diseases with high accuracy and with minimal side effects. At the same time, scientists provide a molecular explanation of hereditary early-onset forms of Alzheimer’s disease, which can attack as soon as thirty years old. The findings of his research, which has been published in the journal Nature Communications, are very encouraging for the future of therapeutic means that could keep Alzheimer’s disease in check.

Alzheimer’s disease is characterized by aggregation of small molecules known as amyloid biological peptides. everything we produce these molecules; play an essential antioxidant role. But in people with Alzheimer’s disease, these peptides are added into toxic plaques in the brain -. “Amyloid plaques” called – That destroy the surrounding neurons

The process begins with a long protein, “APP” which is on the other side of the membrane of the neuron. This protein is cut into pieces by an enzyme, such as a tape is cut with scissors. The initial cut generates a smaller intracellular protein that plays a useful role in neuron. Another cut frees the rest of APP outside the cell -. This part is the amyloid

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For reasons not yet fully understood, the APP protein can be cut in several different places, production of amyloid peptides are of different lengths. Only the forms of amyloid peptide longer carry the risk of plaque aggregation, and people with Alzheimer’s disease produce an abnormally high number of these.

A favorite target of Alzheimer: the gamma secretase

The two next-generation classes compound currently in clinical trials are directed an enzyme that cleaves APP gamma secretase called. So far, our understanding of the mechanisms involved have lacked. However, with this work, researchers at the EPFL were able to shed some more light on it by determining how drug compounds affect gamma secretase and its cleavage activity

In most forms Alzheimer’s disease, abnormally large amounts of long amyloid peptide 42. – – so called because contains 42 amino acids – are formed. The drug compounds change the location on the short gamma secretase APP protein, producing the amyloid peptide 38 instead of 42, which is shorter and does not aggregate in plaques neurotoxic.

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Compared with previous therapeutic efforts, this is considerable progress. in 2010, Phase III clinical trials had to be abandoned because the test compound function inhibited gamma-secretase in all areas, which means that the enzyme was also disabled in essential processes cellular differentiation, the side effects result in bleeding and gastrointestinal cancer skin.

“scientists have been trying to target gamma secretase for treatment of Alzheimer’s disease for more than a decade,” says Patrick Fraering, lead author of the study and Merck Chairman Serono Neurosciences EPFL . “Our work suggests that new generation molecules, through modulation instead of inhibiting the enzyme, could have few, if any, side effects. It is tremendously encouraging.”

New knowledge of hereditary forms of the disease

During their research, the scientists also identified possible causes behind some inherited forms of Alzheimer’s disease . The early onset of Alzheimer’s disease may occur even at thirty years old, with a life expectancy of only a few years. The in vitro experiments and numerical simulations show that in early onset patients, mutations in the APP gene protein modify the way in which the APP is cut by gamma secretase enzyme. This results in overproduction amyloid peptide 42, which then adds in amyloid plaques.

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This research illuminates much that is unknown about Alzheimer’s disease. “We have achieved extraordinary knowledge of how gamma secretase can be modulated” explains co-author Dirk Beher, chief scientific officer Asceneuron, a spin-off from Merck Serono, the biopharmaceutical division of Merck KGaA, Darmstadt, Germany. “This knowledge will be valuable for the development of drugs aimed even better to fight the disease.”


Ecole Polytechnique Federale de Lausanne

Journal reference

  1. Mitko Dimitrov, Jean-René Alattia, Thomas Lemmin, Rajwinder Lehal, Andrzej Fligier, Jemila Houacine, Ishrut Hussain, Freddy Radtke, Matteo Dal Peraro, Dirk Beher, Patrick C. Fraering. Mutations of the APP in Alzheimer’s disease but no γ-secretase modulators affect cleavage epsilon-dependent production AICD . Communications Nature , 2013; 4 DOI: 10.1038 / ncomms3246

This article was originally published on alzheimersweekly, Read the original article here

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