title: Epigenetic suppression of hippocampal BDNF mediates the memory deficiency induced by amyloid fibrils.
abstract: Accumulating evidences demonstrated that epigenetic modification of the expression of specific genes contributed to the pathogenesis of neurological disorders with dementia, including Alzheimer's disease (AD). Emerging reports also found the reduction of hippocampal brain-derived neurotrophic factor (BDNF) in the patients and rodent models of AD, while the mechanism and functional significance remain debated. The present study aims to study the epigenetic mechanism underlying the BDNF reduction and its functional significance in the rats with hippocampal infusion of amyloid fibrils. In the rats injected with amyloid fibrils, significant decreases of BDNF expression and the mRNA of Bdnf exon VI were found in the hippocampal CA1 area. Significantly increased hippocampal HDAC2 expression and its occupancy in the promoter region of Bdnf exon VI were also observed, thus contributing to the histone H3 deacetylation and BDNF suppression in the hippocampal CA1 in the rats injected with amyloid fibrils. Inhibition of HDAC2 activity by trichostatin A substantially recovered the histone H3 acetylation in the promoter region of Bdnf exon VI and BDNF expression, thus mitigating the synaptic dysfunction and memory deficiency induced by amyloid fibrils. These results elucidate the epigenetic mechanism underlying the BDNF reduction induced by amyloid fibrils, and provided novel insights into the pathogenic mechanism of Alzheimer's disease.
authors.affiliation: Department of Geriatrics, The Sixth People's Hospital affiliated to Shanghai Jiao Tong University, Shanghai 200233, China.
authors.forename: Bei-Yun
authors.initials: BY
authors.lastname: Wang
authors.affiliation: Department of Geriatrics, The Sixth People's Hospital affiliated to Shanghai Jiao Tong University, Shanghai 200233, China. Electronic address: zhongyuansh01@163.com.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhong
authors.affiliation: Department of Geriatrics, The Sixth People's Hospital affiliated to Shanghai Jiao Tong University, Shanghai 200233, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Geriatrics, The Sixth People's Hospital affiliated to Shanghai Jiao Tong University, Shanghai 200233, China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Miao
mesh_terms: D000107:Acetylation / Q000187:drug effects; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000235:genetics*; D056547:CA1 Region, Hippocampal / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D044127:Epigenesis, Genetic / Q000187:drug effects*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005106:Exploratory Behavior / Q000187:drug effects; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000633:toxicity*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051381:Rats
chemical_list: D016229:Amyloid beta-Peptides; D019208:Brain-Derived Neurotrophic Factor; D006657:Histones; D006877:Hydroxamic Acids; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C012589:trichostatin A; D056464:Histone Deacetylase 2
keywords: Amyloid fibrils; Brain-derived neurotrophic factor; Histone deacetylase 2; Memory; Synaptic plasticity