Team Sheds light on Alzheimer's mystery

(c) MIT.edu

In work that could lead to new drugs to target Alzheimer’s disease, MIT researchers and colleagues  have shed light on one of the molecular mysteries surrounding this common from of dementia.

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The work, to be reported in the Dec. 11 issue of Neuron, helps explain the perplexing behavior of some cells in the hippocampus, thought to be the center of learning and memory in the brain. In Alzheimer’s disease, stroke and other neurodegenerative conditions, some neurons suddenly start to replicate their DNA as if they were about to divide. That causes them to die.

It is thought that most of the neurons within our brains have formed and exited the cell cycle during gestation and the early postnatal period. No one knows why this sudden reprisal of the cell cycle occurs in adult neurons in Alzheimer’s patients. Now, researcher led by Li-Huei Tsai, the Picower Professor of Neuroscience, are starting to understand the events that precede the death of the cells.

Tsai and colleagues found that these aberrant events occur when an enzyme called HDAC1, which configures chromatin, the structural component of chromosomes, is blocked.

Conversely, “increasing levels of this enzyme protects neurons from re-entering the cell cycle, losing genomic integrity and dying,” said tsai, who has appointments in MIT’s Departement of Brain and Cognitive Sciences and the Picower Institute for learning and Memory and who is also an investigator for the Howard Hughes Medical Institute. “our findings provide insight into how neurons die in neurodegenerative disease and offer a new therapeutic strategy for countering neuronal death.”

Tsai’s finding that HDAC1 is a molecular link between aberrant cell-cycle activity and DNA damage means that the enzyme could be a potential target for therapeutics against diseases and conditions involving neuronal death.

In mice genetically engineered to develop symptoms of Alzheimer’s, Tsai and colleagues found that inactivating the HDAC1 enzyme led to DNA damage and cell death, while reinforcing its activity protected neurons.

Authors include collaborators from Harvard Medical Scholl, University of Central Florida, the Board Institute of MIT and Harvard, Massachusetts General Hospital and McLean Hospital.

This work is supported by the National Institutes of Health and American Heart Association.