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A new avenue for Alzheimer’s
September 2010
by Amy Swinderman  |  Email the author
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CAMBRIDGE, Mass.—In the last two decades, much of Alzheimer's disease research has documented how the amyloid plaques that form in the brain of Alzheimer's patients impact the progress of this degenerative disease. Now, scientists at the Massachusetts Institute of Technology (MIT) are reporting that they have discovered the first link between those plaques and a gene previously implicated in the aging process.

According to the MIT team, the gene, called SIRT1, appears to control production of A-beta peptides, the devastating protein fragments that make up amyloid plaques. Notably, the researchers also showed in a mouse model of Alzheimer's disease that learning and memory deficits improved when SIRT1 was overproduced in the brain, and worsened when SIRT1 was deleted.

These groundbreaking findings were detailed in a study published in the July 23 issue of the journal Cell. According to the study's lead author, Dr. Leonard Guarente, an MIT biology professor, the discovery could lead to the development of drugs that activate SIRT1—a viable strategy to combat Alzheimer's disease, which currently affects an estimated one-third of people who reach the age of 80.

"The past few decades of research have given us a lot of hints that SIRT1 has neuroprotective abilities," says Guarente, who has made great strides in the research of sirtuins, a class of proteins that counter aging and have a wide spectrum of metabolic and stress-tolerance functions.

In 1999, Guarente reported that the yeast version of the gene, SIR2, regulates longevity in yeast. Later work revealed similar effects in worms, mice and rats, and Guarente has made headlines for his hypothesis that caloric restriction slows aging by activation of sirtuins.

SIRT1 has been implicated in protection against metabolic syndrome and diabetes, and sirtuin activators may offer promising new treatments for these increasingly common disorders, according to Guarente.

In this study, Guarente and his MIT colleagues showed that SIRT1 activates the production of an enzyme that cleaves amyloid precursor proteins into harmless fragments instead of the Alzheimer's-associated amyloid peptides. Mice engineered to produce excess SIRT1 had reduced peptide levels, while mice with SIRT1 knocked out showed increased peptide levels.

While the MIT researchers acknowledged they cannot be certain that the reduction of A-beta production in SIRT1 overexpressing mice is the sole mechanism conferring protection against memory decline in mouse models of Alzheimer's, they say they are confident that the increase in the protein ADAM10 and resulting reduction A-beta will benefit the Alzheimer's mice. ADAM10, a target molecule that plays a central role in the development of the molecular processes in Alzheimer's disease, has also been shown to prevent amyloid plaque formation and hippocampal behavioral defects in mouse models of Alzheimer's. ADAM10 mutations have been associated with a reduction in
alpha-secretase in familial, late-onset Alzheimer's.

"To sum it up, our findings clearly indicate that SIRT1 can suppress Alzheimer's disease in a mouse model, which we believe lays out a powerful mechanism for how to protect against the neurodegenerative effects of Alzheimer's," Guarente says. "Our findings indicate that Alzheimer's disease is mitigated by genetic activation of SIRT1. Therefore, we are very eager to develop sirtuin activators that are tailored to cross the blood-brain barrier to treat neurodegenerative diseases."

Sirtuin activators may offer promising new treatments for other neurodegenerative conditions, such as Parkinson's disease, Guarente says. Recent studies have also implicated SIRT1 in tumor protection in some mouse models.

Guarente, who works with GlaxoSmithKline PLC (GSK) and Sirtris, a GSK company developing small-molecule drugs that target sirtuins, says the parties are "very eager" to test drugs designed to pass through the blood-brain barrier in mice before moving on to human trials.

The study, "SIRT1 Suppresses Beta-Amyloid Production by Activating the Alpha-Secretase Gene ADAM10," was co-authored by MIT postdoctoral associates Gizem Donmez and Dena Cohen and junior Diana Wang. The study was funded by the American Parkinson Disease Association fellowship, the National Institutes of Health and the Paul F. Glenn Foundation.
 
 
Code: E091018

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