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Gladstone scientists identify strategy to reduce toxic proteins associated with Alzheimer's disease

SAN FRANCISCO, CASeptember 23, 2010Scientists at the Gladstone Institute of Neurological Disease (GIND) have uncovered new approaches to reduce toxic proteins in Alzheimer's disease (AD) and other neurodegenerative diseases. The results might lead to new treatments for these diseases.

"We examined a protein called tau that has been strongly implicated in Alzheimer's disease," said Li Gan, PhD, senior author on the study. "Tau forms toxic protein aggregations in the brains of Alzheimer patients."

Tau is a common protein in the central nervous system where it helps to stabilize the cytoskeleton that supports the structure of neurons. Mutations in tau cause neurodegeneration in human brains, and tau modified by the addition of phosphate groups (p-tau) forms aggregates and damages neurons. Strategies to get rid of p-tau from neurons are sorely needed.

"We do know that levels of an enzyme called SIRT1 are reduced in AD brains and this reduction is associated with the amount of tau aggregates. We also know that SIRT1 is protective in a mouse model of neurodegeneration," said Dr. Gan. "But we didn't know how all of this fits together."

One important clue was that SIRT1 is a deacetylase, an enzyme that removes acetyl groups from proteins. Like phosphorylation, acetylation regulates many different cellular functions. "Because of this, we wanted to know if tau is acetylated," said Dr. Gan.

In this study, published in the September 23 issue of the journal Neuron, Dr. Gan's group report that, in fact, tau is acetylated. Furthermore, they found that patients at early and moderate stages of AD had elevated levels of tau acetylation.

The researchers showed that inhibiting SIRT1 increased levels of both the acetylated tau and the p-tau in neurons grown in culture dishes.

The team then wondered if inhibiting the production of acetylated tau would have an effect. Importantly, when they inhibited p300, an enzyme known to add acetyl groups to proteins, the neurons had much less acetylated tau and toxic p-tau.

The research shows that the clearance of the toxic p-tau is blocked by acetylation. "The abnormally high levels of acetylation at early stages of the disease could lead to the formation of toxic protein aggregates in AD and other neurodegenerative diseases," explained Dr. Gan.

"This study suggests that interfering with tau acetylation may be a new approach for reducing tau-related pathology," said Dr. Mucke, GIND director. "In fact, Dr. Gan and her team have already identified a small molecule compound that eliminates toxic p-tau in neurons. It might represent a new class of anti-AD drugs."


Contact: Valerie Tucker
Gladstone Institutes

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