An epigenetic blockade of cognitive functions in the neurodegenerating brain

Abstract

Histone deacetylase 2 is shown to suppress genes involved in cognitive function epigenetically, potentially opening the door to treatments for Alzheimer’s and other neurodegenerative diseases by developing HDAC2-selective inhibitors. What causes the cognitive decline associated with neurodegenerative diseases is not fully understood. This study reveals a novel epigenetic mechanism by which Alzheimer's-disease-related neurotoxicity reduces the expression of genes necessary for neural plasticity. In two mouse models of Alzheimer's disease — and in post-mortem samples from human subjects — expression of the epigenetic regulator histone deacetylase 2 (HDAC2) is elevated. Reversing the upregulation of HDAC2 by short-hairpin-RNA-mediated knockdown in mice restores the expression of HDAC2 target genes and abolishes the neurodegeneration-associated memory impairment. Cognitive decline is a debilitating feature of most neurodegenerative diseases of the central nervous system, including Alzheimer’s disease1. The causes leading to such impairment are only poorly understood and effective treatments are slow to emerge2. Here we show that cognitive capacities in the neurodegenerating brain are constrained by an epigenetic blockade of gene transcription that is potentially reversible. This blockade is mediated by histone deacetylase 2, which is increased by Alzheimer’s-disease-related neurotoxic insults in vitro, in two mouse models of neurodegeneration and in patients with Alzheimer’s disease. Histone deacetylase 2 associates with and reduces the histone acetylation of genes important for learning and memory, which show a concomitant decrease in expression. Importantly, reversing the build-up of histone deacetylase 2 by short-hairpin-RNA-mediated knockdown unlocks the repression of these genes, reinstates structural and synaptic plasticity, and abolishes neurodegeneration-associated 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.