Physicians can treat the symptoms of Alzheimer’s disease and other neurodegenerative disorders, but there is no way to prevent or reverse the underlying degeneration and death of neurons that characterize these diseases. Now research by scientists at Harvard and MIT suggests a potential new therapeutic approach.
The scientists have shown that a gene called SIRT1 and a plant compound found in red wine called resveratrol can protect against neuron degeneration in a mouse model of Alzheimer’s disease and amyotrophic lateral sclerosis. The researchers demonstrated that activating SIRT1 and injecting resveratrol, which have both been previously associated with life-span extension in lower organisms, can also prevent cognitive problems in the mice.
The mice used in the study develop an approximation of human neurodegenerative disease over a period of weeks. As neurons in their brains die and lose connections, their spatial learning is impaired, and the mice develop difficulty associating cause and effect. Treatment with resveratrol reduced the death and degeneration of neurons in these mice and also restored their learning abilities to a level comparable to that of normal mice not suffering neurodegeneration. “Thus, resveratrol is not only neuroprotective, it also improves cognitive function after severe neurodegeneration,” says Li-Huei Tsai, the professor of neuroscience at MIT who led the research with David Sinclair, a professor of pathology at Harvard. Tsai says this improvement in function suggests that resveratrol has potential for treating human neurodegenerative diseases.
Sinclair cofounded Sirtris, a company based in Cambridge, MA, that’s developing resveratrol-like therapies for a range of diseases, including type 2 diabetes and another metabolic disorder, called MELAS syndrome. Tsai is a scientific advisor to Sirtris.
The study is the first to suggest that resveratrol could actually improve cognitive function in patients with neurodegenerative diseases. “Generally, SIRT1 has been observed to be neuroprotective,” says Leonard Guarente, the professor of biology at MIT who uncovered the connection between life span and the yeast equivalent to SIRT1 about 10 years ago. What’s new about Tsai and Sinclair’s work, he says, is its demonstration that activating SIRT1 prevents cognitive decline in mice with neurodegenerative disease. The study shows that “resveratrol can protect against memory loss and learning decline,” says Guarente, who was not involved with the research.
Guarente says the study suggests that compounds that can activate SIRT1 could be used to treat neurodegenerative disease in humans as long as they can pass through the blood-brain barrier. This membrane surrounding and protecting the brain from chemicals in the blood presents a major challenge to any researcher developing drugs that target the brain. Mice in the study received injections of resveratrol directly into blood vessels in their brains, which would not be practical in human patients.
The Harvard/MIT study could also shed light on the mechanisms behind Alzheimer’s. Most studies of Alzheimer’s disease focus on the toxic, malformed proteins that build up in afflicted neurons; Tsai and Sinclair’s study did not. “This research takes a path less traveled,” says Stephen Snyder, director of the Etiology of Alzheimer’s Disease Program at the National Institute on Aging.
Indeed, some researchers have suggested that Alzheimer’s and other diseases characterized by neuron death might be “two-hit phenomena” caused not only by protein buildup but also by malfunctions in the molecular pathways that suppress tumors. SIRT1 is connected with tumor suppression, Snyder says, and may point to a second hit necessary for the development of Alzheimer’s. Although he cautions that this is early work, Snyder says that Sinclair and Tsai “seem to have their hands on a potential mechanism.”
Sinclair and Tsai’s findings add to growing evidence that resveratrol could have a broad range of beneficial health effects, from treating metabolic diseases like obesity and diabetes to protecting against neurodegenerative disorders. Previous studies have shown that resveratrol extends life span in yeast, roundworms, fruit flies, and fish. (See “A Life-Extending Pill for Fat Mice.”) Researchers don’t know exactly how it causes health benefits and prolongs life span, but it appears to activate SIRT1. This gene is one of a family of genes called sirtuins that many researchers believe are master regulators of the aging process. By activating sirtuins, Sinclair, Guarente, and other researchers aim not to extend human life but to create new therapies for the diseases of aging. (See “Fountain of Health.”)
“I’m optimistic about SIRT1 activation as a therapeutic,” says Sinclair. “[Its effect] seems to be so broad, as though the gene can keep cells alive under very different types of stress.” Now SIRT1 activation appears to keep neurons alive and reverse cognitive decline, providing further reason for Sirtris and other pharmaceutical companies to continue exploring this therapeutic approach.
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