title: Epigenetic regulation of HDAC1 SUMOylation as an endogenous neuroprotection against Aβ toxicity in a mouse model of Alzheimer's disease.
abstract: Amyloid-β (Aβ) produces neurotoxicity in the brain and causes neuronal death, but the endogenous defense mechanism that is activated on Aβ insult is less well known. Here we found that acute Aβ increases the expression of PIAS1 and Mcl-1 via activation of MAPK/ERK, and Aβ induction of PIAS1 enhances HDAC1 SUMOylation in rat hippocampus. Knockdown of PIAS1 decreases endogenous HDAC1 SUMOylation and blocks Aβ induction of Mcl-1. Sumoylated HDAC1 reduces it association with CREB, increases CREB binding to the Mcl-1 promoter and mediates Aβ induction of Mcl-1 expression. Transduction of SUMO-modified lenti-HDAC1 vector to the hippocampus of APP/PS1 mice rescues spatial learning and memory deficit and long-term potentiation impairment in APP/PS1 mice. It also reduces the amount of amyloid plaque and the number of apoptotic cells in CA1 area of APP/PS1 mice. Meanwhile, HDAC1 SUMOylation decreases HDAC1 binding to the neprilysin promoter. These results together reveal an important role of HDAC1 SUMOylation as a naturally occurring defense mechanism protecting against Aβ toxicity and provide an alternative therapeutic strategy against AD.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Chih Chieh
authors.initials: CC
authors.lastname: Tao
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Wei Lun
authors.initials: WL
authors.lastname: Hsu
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Yun Li
authors.initials: YL
authors.lastname: Ma
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.|Neuroscience Program in Academia Sinica, Taipei, Taiwan.
authors.forename: Sin Jhong
authors.initials: SJ
authors.lastname: Cheng
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.|Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Eminy Hy
authors.initials: EH
authors.lastname: Lee
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002070:Butadienes / Q000494:pharmacology; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D015870:Gene Expression / Q000187:drug effects; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D000066829:Neuroprotection / Q000187:drug effects*; D009570:Nitriles / Q000494:pharmacology; D011485:Protein Binding; D050828:Protein Inhibitors of Activated STAT / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D058207:Sumoylation
chemical_list: D016229:Amyloid beta-Peptides; D002070:Butadienes; D009570:Nitriles; C494211:Pias1 protein, mouse; D050828:Protein Inhibitors of Activated STAT; C113580:U 0126; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1