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

Authors
  • Wang, David B1
  • Kinoshita, Chizuru1
  • Kinoshita, Yoshito1
  • Sopher, Bryce L2
  • Uo, Takuma1, 3
  • Lee, Rona J1
  • Kim, Joon Kyu1
  • Murphy, Sean P1
  • Dirk Keene, C4
  • Garden, Gwenn A2, 4
  • Morrison, Richard S1
  • 1 Department of Neurological Surgery, University of Washington School of Medicine, Seattle, WA, 98195-6470.
  • 2 Department of Neurology, University of Washington School of Medicine, Seattle, WA, 98195-6465.
  • 3 Current Affiliation-Department of Medicine, University of Washington School of Medicine, Seattle, WA, 98195-6420.
  • 4 Department of Pathology, University of Washington School of Medicine, Seattle, WA, 98195-7470.
Type
Published Article
Journal
Brain Pathology
Publisher
Wiley (Blackwell Publishing)
Publication Date
Mar 01, 2019
Volume
29
Issue
2
Pages
164–175
Identifiers
DOI: 10.1111/bpa.12647
PMID: 30028551
Source
Medline
Language
English
License
Unknown

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. © 2018 International Society of Neuropathology.

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