title: ApoE4 and Aβ Oligomers Reduce BDNF Expression via HDAC Nuclear Translocation.
abstract: Apolipoprotein E4 (ApoE4) is a major genetic risk factor for several neurodegenerative disorders, including Alzheimer's disease (AD). Epigenetic dysregulation, including aberrations in histone acetylation, is also associated with AD. We show here for the first time that ApoE4 increases nuclear translocation of histone deacetylases (HDACs) in human neurons, thereby reducing BDNF expression, whereas ApoE3 increases histone 3 acetylation and upregulates BDNF expression. Amyloid-β (Aβ) oligomers, which have been implicated in AD, caused effects similar to ApoE4. Blocking low-density lipoprotein receptor-related protein 1 (LRP-1) receptor with receptor-associated protein (RAP) or LRP-1 siRNA abolished the ApoE effects. ApoE3 also induced expression of protein kinase C ε (PKCε) and PKCε retained HDACs in the cytosol. PKCε activation and ApoE3 supplementation prevented ApoE4-mediated BDNF downregulation. PKCε activation also reversed Aβ oligomer- and ApoE4-induced nuclear import of HDACs, preventing the loss in BDNF. ApoE4 induced HDAC6-BDNF promoter IV binding, which reduced BDNF exon IV expression. Nuclear HDAC4 and HDAC6 were more abundant in the hippocampus of ApoE4 transgenic mice than in ApoE3 transgenic mice or wild-type controls. Nuclear translocation of HDA6 was also elevated in the hippocampus of AD patients compared with age-matched controls. These results provide new insight into the cause of synaptic loss that is the most important pathologic correlate of cognitive deficits in AD.
authors.affiliation: Blanchette Rockefeller Neurosciences Institute, Morgantown, West Virginia 26505 asen@brni.org.
authors.forename: Abhik
authors.initials: A
authors.lastname: Sen
authors.affiliation: Blanchette Rockefeller Neurosciences Institute, Morgantown, West Virginia 26505.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Nelson
authors.affiliation: Blanchette Rockefeller Neurosciences Institute, Morgantown, West Virginia 26505.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Alkon
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D001921:Brain / Q000473:pathology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002466:Cell Nucleolus / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D002784:Cholesterol / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000648:ultrastructure*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D034622:RNA Interference / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D019208:Brain-Derived Neurotrophic Factor; C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D002784:Cholesterol; D011493:Protein Kinase C; D006655:Histone Deacetylases
keywords: Alzheimer's disease; ApoE; BDNF; LRP1; PKC; histone deacetylase