An epigenetic blockade of cognitive functions in the neurodegenerating brain

Abstract

Cognitive decline is a debilitating feature of most neurodegenerative diseases of the central nervous system, including Alzheimer’s disease (AD)1. 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 (HDAC) 2, which is increased by AD-related neurotoxic insults in vitro, in two mouse models of neurodegeneration, and in AD patients. HDAC2 associates with and reduces the histone acetylation of genes important for learning and memory, which show a concomitant decrease in expression. Importantly, reversing the buildup of HDAC2 by shRNA-mediated knockdown unlocks the repression of these genes, re-instates structural and synaptic plasticity, and abolishes neurodegeneration-associated memory impairments. These findings advocate for the development of HDAC2-selective inhibitors, and suggest that cognitive capacities following neurodegeneration are not entirely lost, but merely impaired by this epigenetic blockade.

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

“…Notably, amongst the 14 HDAC isoforms described so far, class I HDAC2 and HDAC3 (but not HDAC1) have been associated with the promoters of genes implicated in synaptic plasticity [183,213], potentially explaining some of the HDACi beneficial effects on memory formation. HDAC2 was further increased in AD postmortem brains [214]. Interestingly, at least one wild-type allele of cbp was required to mediate the effects of HDAC inhibition on memory functions [215].…”

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

“…Histone acetylation is a major topic in the AD field, as it was found to be drastically decreased in both human (Zhang et al, 2012) and mouse models of AD (Gräff et al, 2012). Indirectly enhancing histone acetylation by chronic inhibition of histone deacetylases (HDACs) was able to reverse the cognitive deficits in AD mouse model (Kilgore et al, 2010) and also in aging mouse (Benito et al, 2015).…”

Propofol exposure during early gestation impairs learning and memory in rat offspring by inhibiting the acetylation of histone

“…HATs acetylate multiple lysine residues on histones, and different acetylated sites result in different downstream biological effects. H3K14 and H4K12 acetylation have been shown to play a crucial part in learning, memory and synaptic plasticity 35. The results showed that propofol exposure during pregnancy up‐regulated HDAC2 protein expression in offspring rat's hippocampus (Figure 6, P < .05), whereas decreased the acetylation levels of H3K14 and H4K12 significantly (Figure 5, P < .05).…”

“…Reversing the build‐ up of HDAC2 by short‐hairpin‐RNA ‐mediated knockdown activated these genes, reinstated structural and synaptic plasticity and abolished the neurodegeneration‐associated memory impairments. Abolished the memory impairments in connection with neurodegeneration 35. Our earlier study suggested that maternal isoflurane anaesthesia during third trimester impairs the spatial learning and memory of the offspring rats, and its mechanism in connection with the up‐regulation of HDAC2 mRNA and subsequent inhibits the expression of CREB mRNA and NR2B, while HDAC2 inhibition reversed these changes 30.…”

“…Decrease in synaptophysin is implicated in learning and memory impairment 1, 4, 5. Graff et al35 demonstrated that HDAC2 overexpression reduced synaptophysin protein level and caused memory impairments, HDAC2 inhibition reversed the effects. As synaptophysin is one of the CREB target genes,53 we detected the expression of synaptophysin in the present study.…”