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The repression of gene activity in the brain may be reversible

Saturday 10 March 2012

Researchers from the Massachusetts Institute of Technology (MIT) have found that repression of gene activity in the brain appears to be an early event in people with Alzheimer's disease. They also found that this blockade and its effects on memory are treatable.

The study was led by Li-Huei Tsai, Ph.D., director of MIT's Picower Institute for Learning and Memory. Her team found that a protein called histone deacetylase 2 (HDAC2) accumulates in the brain early in the course of Alzheimer's disease, both in mouse models and in people with the disease.

HDAC2 is known to tighten up spools of DNA, effectively locking down the genes within and reducing their activity. In the mice, the increase in HDAC2 appears to produce a blockade of genes involved in learning and memory.

Gene therapy to reduce the levels of HDAC2 prevented the blockade of gene activity. The treatment also prevented learning and memory impairments in the mice. It did not prevent neuronal death, but it did enhance neuroplasticity - the ability of neurons to form new connections.

Dr. Tsai also examined HDAC2 levels in autopsied brain tissue from 19 people with Alzheimer’s at different stages of the disease and from seven healthy controls. Even in its earliest stages, the disease was associated with higher HDAC2 levels in the learning and memory regions of the brain.
 
 "We think that the blockade of gene expression plays a very important role in the cognitive decline associated with Alzheimer's disease," said Dr. Tsai. "The good news is that the blockade is potentially reversible."

Dr. Tsai theorizes that HDAC2 is brought into play by beta-amyloid. She and her team found that exposing mouse neurons to beta-amyloid caused them to produce more HDAC2.
 
 "We think beta-amyloid triggers a cascade of damaging reactions. Once of these is to activate HDAC2, which in turn blocks the expression of genes needed for brain plasticity. Once this blockade is in place, it may have a more systemic, chronic effect on the brain," she said.

http://www.nature.com/nature/journal/v483/n7388/full/nature10849.html

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