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Novel role of protein in generating amyloid-beta peptide
Date:4/27/2009

A defining hallmark of Alzheimer's disease is the accumulation of the amyloid β protein (Aβ), otherwise known as "senile plaques," in the brain's cortex and hippocampus, where memory consolidation occurs. Researchers at the University of California, San Diego School of Medicine have identified a novel protein which, when over-expressed, leads to a dramatic increase in the generation of Aβ. Their findings, which indicate a potential new target to block the accumulation of amyloid plaque in the brain, will be published in the May 1 issue of the Journal of Biological Chemistry.

"The role of the multi-domain protein, RANBP9, suggests a possible new therapeutic target for Alzheimer's disease," said David E. Kang, PhD, assistant professor of neurosciences at UC San Diego and director of this study.

The neurotoxic protein Aβ is derived when the amyloid precursor protein (APP) is "cut" by two enzymes, β-secretase (or BACE) and γ-secretase (or Presenilin complex.) However, inhibiting these enzymes in order to stop the amyloid cascade has many negative side effects, as these enzymes also have various beneficial uses in brain cells. So the researchers looked for an alternative way to block the production of amyloid beta.

In order for cleavage to occur, the APP needs to travel to cholesterol-enriched sites within the cell membrane called RAFTS, where APP interacts with the two enzymes. It is this contact that the researchers sought to block.

Kang explains that the researchers identified the RANBP9 protein by studying low density lipoprotein receptor-related protein (LRP), a protein that rapidly shuttles Aβ out of the brain and across the blood-brain barrier to the body, where it breaks down into harmless waste products. A small segment of LRP can also stimulate Aβ generation, and the scientists narrowed this segment down to a 37-amino-acid stretch that can lead to changes in Aβ.<
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Contact: Debra Kain
ddkain@ucsd.edu
619-543-6163
University of California - San Diego
Source:Eurekalert

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