Epigenetic Blockade May Impair Cognition in Alzheimer's

Histone deacetylase 2 reduces histone acetylation of genes involved in learning, memory in mice

THURSDAY, March 1 (HealthDay News) -- An epigenetic blockade may be responsible for cognitive impairment in Alzheimer's disease, and reversing this blockade improves cognitive abilities in mouse models of Alzheimer-like neurodegeneration, according to an experimental study published online Feb. 29 in Nature.

Noting that reduced histone acetylation has been associated with cognitive decline, and that histone deacetylase 2 (HDAC2) is known to negatively regulate memory in healthy mice, Johannes Gräff, Ph.D., from the Massachusetts Institute of Technology in Cambridge, and colleagues investigated whether HDAC2 mediates cognitive deficits associated with neurodegeneration in a mouse model of Alzheimer's disease.

The researchers found that HDAC2 was significantly elevated in the hippocampi in mouse models of Alzheimer-like neurodegeneration, by Alzheimer's-disease-related neurotoxic insults in vitro, and in patients with Alzheimer's disease. HDAC2 reduced histone acetylation of genes important for learning and memory, decreasing their expression. Short-hairpin-RNA-mediated knockdown reversed this reduction, restored structural and synaptic plasticity, and abolished the memory impairments.

"These findings advocate for the development of selective inhibitors of histone deacetylase 2 and suggest that cognitive capacities following neurodegeneration are not entirely lost, but merely impaired by this epigenetic blockade," Gräff and colleagues conclude.

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