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When they examined the acetylation patterns of brain histones in these two groups of mice, researchers discovered that the patterns differed dramatically. With that finding, complemented by prior reports of the beneficial effect of HDAC inhibitors on learning and memory, the Tsai team was motivated to test such agents on its mouse model. They discovered that administering an HDAC inhibitor—sodium butyrate or trichostatin A—to the mice instead of environmental enrichment was enough to restore lost memories.
"The brains of the treated mice didn't look any bigger and the number of cells in the brain didn't look significantly different from those of untreated mice," says Tsai. "But it seemed that the existing neurons were more active in communicating with each other and making more synapses."
Tsai cites recent studies on an HDAC called SIR2, which shows anti-aging properties in many organisms. "Alzheimer's disease is a typical product of aging," she says. "So to me, it's quite logical that the next question was whether SIR2 might also be beneficial in treating this illness." With her colleague David Sinclair's research team at Harvard Medical School, Tsai's group tested that notion using the MIT mice and then reported their findings last June in the online version of The EMBO Journal. The overexpression of SIRT1—the human version of SIR2—in the mice not only protected them from neurodegeneration but preserved their cognitive and memory functions as well.
The scientists also tested the neuroprotective effects of resveratrol, the compound in red wine that has attracted considerable scientific and media attention for its possible anti-aging properties. They found that resveratrol, an activator of SIRT1, offered the mice substantial protection from neurodegeneration and preserved their learning ability. Just how SIRT1 protects the brain is unclear to Tsai, since the enzyme targets many other protein substrates besides histones, but her team is trying to pin down its biochemical role in the brain.
Given these experimental results, Tsai is "cautiously optimistic" that new drugs for preventing, even reversing, the effects of Alzheimer's disease may become realities in the not-too-distant future. "I can't tell you it's a year or two from now," she says, "but I don't think it will be as long as 10 years."