An Epigenetic Blockade of Cognitive Functions in the Neurodegenerating Brain

Cognitive decline is a debilitating feature of most neurodegenerative diseases of the central nervous system, including Alzheimer’s disease. The causes leading to such impairment are only poorly understood and effective treatments are slow to emerge. However, a team of researchers including Dr. Ivana Delalle, associate professor in pathology and laboratory medicine and neurology along with Patricia Kao, a 4th year PhD candidate in pathology and laboratory medicine, have shown that cognitive capacities in the neurodegenerating brain are constrained by an epigenetic blockade of gene transcription that is potentially reversible. Their findings recently appeared on-line in the journal Nature.

According to the researchers this blockade is mediated by histone deacetylase 2, which is increased by Alzheimer’s-disease-related neurotoxic insults in vitro, in two 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.

“We have shown for the for first time in human post-mortem brain samples of patients at different stages of Alzheimer’s disease (AD) associated pathology, histone deacetylase (HDAC) 2 levels to be elevated, suggesting that a epigenetic blockade of cognitive functions documented in models of AD might be at play in the human brains inflicted by AD as well,” explained Delalle.

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.