Neuronal susceptibility to beta‐amyloid toxicity and ischemic injury involves histone deacetylase‐2 regulation of endophilin‐B1

Abstract

Histone deacetylases (HDACs) catalyze acetyl group removal from histone proteins, leading to altered chromatin structure and gene expression. HDAC2 is highly expressed in adult brain, and HDAC2 levels are elevated in Alzheimer's disease (AD) brain. We previously reported that neuron-specific splice isoforms of Endophilin-B1 (Endo-B1) promote neuronal survival, but are reduced in human AD brain and mouse models of AD and stroke. Here, we demonstrate that HDAC2 suppresses Endo-B1 expression. HDAC2 knockdown or knockout enhances expression of Endo-B1. Conversely, HDAC2 overexpression decreases Endo-B1 expression. We also demonstrate that neurons exposed to beta-amyloid increase HDAC2 and reduce histone H3 acetylation while HDAC2 knockdown prevents Aβ induced loss of histone H3 acetylation, mitochondrial dysfunction, caspase-3 activation, and neuronal death. The protective effect of HDAC2 knockdown was abrogated by Endo-B1 shRNA and in Endo-B1-null neurons, suggesting that HDAC2-induced neurotoxicity is mediated through suppression of Endo-B1. HDAC2 overexpression also modulates neuronal expression of mitofusin2 (Mfn2) and mitochondrial fission factor (MFF), recapitulating the pattern of change observed in AD. HDAC2 knockout mice demonstrate reduced injury in the middle cerebral artery occlusion with reperfusion (MCAO/R) model of cerebral ischemia demonstrating enhanced neuronal survival, minimized loss of Endo-B1, and normalized expression of Mfn2. These findings support the hypothesis that HDAC2 represses Endo-B1, sensitizing neurons to mitochondrial dysfunction and cell death in stroke and AD.

Alcohol Extracts From Ganoderma lucidum Delay the Progress of Alzheimer’s Disease by Regulating DNA Methylation in Rodents

“…The importance of methylation in aging is linked with another epigenetic modification, histone acetylation (Zeng et al, 2015; Wang et al, 2018). A global reduction in gene expression, referred to as an epigenetic blockade, is observed in AD and may be regulated by post-translational modifications of histones (Gräff et al, 2012).…”

3-<em>n</em>-butylphthalide exerts neuroprotective effects by enhancing anti-oxidation and attenuating mitochondrial dysfunction in an in vitro model of ischemic stroke

“…[6][7][8][9] Mitochondrial dysfunction appears to contribute to ischemic stroke by increasing oxidative stress, perturbing calcium homeostasis and inducing neuronal apoptosis. 10 correspondence: Jianfeng Zhang Oxygen and glucose deprivation (OGD), one of the most important pathogenic mechanisms in cerebral infarction, 11 is widely used in vitro as a model of ischemic stroke. OGD induces oxidative stress and formation of ROS, which damage cerebral neurons.…”

Reduction of HDAC2 expression in human induced pluripotent stem cell derived neurons improves neuronal maturation, mitochondrial dynamics and cellular neurodegenerative disease phenotypes

“…Our previous work demonstrates a role for HDAC2 in regulation of mitochondrial dynamics in primary mouse cortical neurons [13]. While class I HDACs, HDAC 1 and HDAC2, are required for neuronal specification from neural progenitor cells [20] and control synapse function and maturation [8] in mice, HDAC2 expression and regulation of cellular processes in living, human neurons has not yet been examined.…”

“…We observed that HDAC2 protein expression is present at all time points but levels decline as neuronal differentiation proceeds ( Figure 1B, C). Our previous work in mouse primary cortical neurons demonstrated that HDAC2 expression negatively impacts the expression of Endophilin-B1 (Endo-B1), a multifunctional protein involved in mitochondrial dynamics [13]. In neurons, Endo-B1 is alternatively spliced yielding neuron-specific Endo-B1b and Endo-B1c as major isoforms relative to the ubiquitously expressed Endo-B1a [26].…”

“…Endo-B1a=ubiquitous isoform, Endo-B1b/c=neuron-specific isoforms. Note: Endo-B1b and Endo-B1c cannot be resolved on western blot [13,26,30] and are indicated as Endo-B1b/c.…”