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New Plaque-Boosting Protein a Possible Alzheimer Target

New Plaque-Boosting Protein a Possible Alzheimer Target The discovery of a novel protein that boosts production of amyloid-β in the brain offers scientists a new target as they search for effective therapies to treat Alzheimer disease. In order to develop strategies to reduce amyloid-β, the main constituent of the characteristic plaques of Alzheimer disease, some scientists have attempted to elucidate the events surrounding the generation of amyloid-β from amyloid precursor protein. In the new work, researchers at Rockefeller University in New York City identified the novel brain protein, γ-secretase activating protein (GSAP), and discovered that it selectively increases the production of amyloid-β through its interactions with the protease γ-secretase and the latter's substrate, the amyloid precursor protein carboxy-terminal fragment. Using a mouse model of Alzheimer disease, the research team showed that knocking down GSAP reduced levels of amyloid-β as well as plaque development (He G et al. Nature. 2010;467[7311]:95-99). “Our findings reveal that [GSAP] is a potential target for a new class of anti-amyloid therapies,” said Paul Greengard, PhD, in a statement. Greengard, a Nobel laureate, heads the Rockefeller Laboratory of Molecular and Cellular Neuroscience. An important feature of GSAP is its selective nature: it does not interact with another substrate of γ-secretase, a molecule called Notch that plays key roles in the hematopoietic and immune systems. Earlier studies from the same research team also had shown that the cancer drug imatinib decreases amyloid-β without affecting Notch. Now the researchers have gone a step further, showing that imatinib's ability to inhibit amyloid-β formation occurs by binding to GSAP and preventing it from activating γ-secretase. But imatinib cannot cross the blood-brain barrier, ruling it out as a potential Alzheimer therapy. “Anti-amyloid therapeutic drugs represent a valid approach to treating Alzheimer's disease, but their inability to accumulate in the brain has limited their usefulness,” said Greengard. “The development of compounds that work like [imatinib], but have the ability to pass the blood-brain barrier and target GSAP could revolutionize the treatment of this disease,” he added. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA American Medical Association

New Plaque-Boosting Protein a Possible Alzheimer Target

JAMA , Volume 304 (13) – Oct 6, 2010

New Plaque-Boosting Protein a Possible Alzheimer Target

Abstract

The discovery of a novel protein that boosts production of amyloid-β in the brain offers scientists a new target as they search for effective therapies to treat Alzheimer disease. In order to develop strategies to reduce amyloid-β, the main constituent of the characteristic plaques of Alzheimer disease, some scientists have attempted to elucidate the events surrounding the generation of amyloid-β from amyloid precursor protein. In the new work, researchers at Rockefeller...
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Publisher
American Medical Association
Copyright
Copyright © 2010 American Medical Association. All Rights Reserved.
ISSN
0098-7484
eISSN
1538-3598
DOI
10.1001/jama.2010.1390
Publisher site
See Article on Publisher Site

Abstract

The discovery of a novel protein that boosts production of amyloid-β in the brain offers scientists a new target as they search for effective therapies to treat Alzheimer disease. In order to develop strategies to reduce amyloid-β, the main constituent of the characteristic plaques of Alzheimer disease, some scientists have attempted to elucidate the events surrounding the generation of amyloid-β from amyloid precursor protein. In the new work, researchers at Rockefeller University in New York City identified the novel brain protein, γ-secretase activating protein (GSAP), and discovered that it selectively increases the production of amyloid-β through its interactions with the protease γ-secretase and the latter's substrate, the amyloid precursor protein carboxy-terminal fragment. Using a mouse model of Alzheimer disease, the research team showed that knocking down GSAP reduced levels of amyloid-β as well as plaque development (He G et al. Nature. 2010;467[7311]:95-99). “Our findings reveal that [GSAP] is a potential target for a new class of anti-amyloid therapies,” said Paul Greengard, PhD, in a statement. Greengard, a Nobel laureate, heads the Rockefeller Laboratory of Molecular and Cellular Neuroscience. An important feature of GSAP is its selective nature: it does not interact with another substrate of γ-secretase, a molecule called Notch that plays key roles in the hematopoietic and immune systems. Earlier studies from the same research team also had shown that the cancer drug imatinib decreases amyloid-β without affecting Notch. Now the researchers have gone a step further, showing that imatinib's ability to inhibit amyloid-β formation occurs by binding to GSAP and preventing it from activating γ-secretase. But imatinib cannot cross the blood-brain barrier, ruling it out as a potential Alzheimer therapy. “Anti-amyloid therapeutic drugs represent a valid approach to treating Alzheimer's disease, but their inability to accumulate in the brain has limited their usefulness,” said Greengard. “The development of compounds that work like [imatinib], but have the ability to pass the blood-brain barrier and target GSAP could revolutionize the treatment of this disease,” he added.

Journal

JAMAAmerican Medical Association

Published: Oct 6, 2010

Keywords: alzheimer's disease,staphylococcal protein a

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