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Protein linked to aging may boost memory and learning ability

Discovery could lead to new drugs to fight Alzheimer’s and other neurological diseases.
Crystallographic structure of yeast sir2 complexed with ADP and a histone H4 peptide.
Crystallographic structure of yeast sir2 complexed with ADP and a histone H4 peptide.
Li-Huei Tsai, director of MIT's Picower Institute for Learning and Memory
Li-Huei Tsai, director of MIT's Picower Institute for Learning and Memory
Photo: Donna Coveney

Over the past 20 years, biologists have shown that proteins called sirtuins can slow the aging process in many animal species.

Now an MIT team led by Professor Li-Huei Tsai has revealed that sirtuins can also boost memory and brainpower — a finding that could lead to new drugs for Alzheimer’s disease and other neurological disorders.

Sirtuins’ effects on brain function, including learning and memory, represent a new and somewhat surprising role, says Tsai, the Picower Professor of Neuroscience and an investigator of the Howard Hughes Medical Institute. “When you review the literature, sirtuins are always associated with longevity, metabolic pathways, calorie restriction, genome stability, and so on. It has never been shown to play a role in synaptic plasticity,” she says.

Synaptic plasticity — the ability of neurons to strengthen or weaken their connections in response to new information — is critical to learning and memory. Potential drugs that enhance plasticity by boosting sirtuin activity could help patients with neurological disorders such as Alzheimer’s, Parkinson’s and Huntington’s diseases, says Tsai.

A protein with many roles

Sirtuins have received much attention in recent years for their life-span-boosting potential, and for their link to resveratrol, a compound found in red wine that has shown beneficial effects against cancer, heart disease and inflammation in animal studies.

MIT Biology Professor Leonard Guarente discovered about 15 years ago that the SIR2 gene regulates longevity in yeast. Later work revealed similar effects in worms, mice and rats.

More recently, studies have shown that one mammalian version of the gene, SIRT1, protects against oxidative stress (the formation of highly reactive molecules that can damage cells) in the heart and maintains genome stability in multiple cell types. SIRT1 is thought to be a key regulator of an evolutionarily conserved pathway that enhances cell survival during times of stress, especially a lack of food.

In 2007, Tsai and her colleagues showed that sirtuins (the proteins produced by SIR or SIRT genes) protect neurons against neurodegeneration caused by disorders such as Alzheimer’s. They also found that sirtuins improved learning and memory, but believed that might be simply a byproduct of the neuron protection.

However, Tsai’s new study, funded by National Institutes of Health, the Simons Foundation, the Swiss National Science Foundation and the Howard Hughes Medical Institute, shows that sirtuins promote learning and memory through a novel pathway, unrelated to their ability to shield neurons from damage. The team demonstrated that sirtuins enhance synaptic plasticity by manipulating tiny snippets of genetic material known as microRNA, which have recently been discovered to play an important role in regulating gene expression.

Specifically, the team showed that sirtuins block the activity of a microRNA called miR-134, which normally halts production of CREB, a protein necessary for plasticity. When miR-134 is inhibited, CREB is free to help the brain adjust its synaptic activity.

Mice with the SIRT1 gene missing in the brain performed poorly on several memory and learning tests, including object-recognition tasks and a water maze.

“Activation of sirtuins can directly enhance cognitive function,” says Tsai. “This really suggests that SIRT1 is a very good drug target, because it can achieve multiple beneficial effects.”

Raul Mostoslavsky, assistant professor of medicine at Harvard Medical School, says the findings do suggest that activating SIRT1 could benefit patients with neurodegenerative diseases. “However, we will need to be very cautious before jumping to conclusions,” he says, “since SIRT1 has (multiple) effects in multiple cells and tissues, and therefore targeting specifically this brain function will be quite challenging.”

Tsai and her colleagues are now studying the mechanism of SIRT1’s actions in more detail, and are also investigating whether sirtuin genes other than SIRT1 influence memory and learning.

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