title: Epigenetic mechanisms linking diabetes and synaptic impairments.
abstract: Diabetes is one of the major risk factors for dementia. However, the molecular mechanism underlying the risk of diabetes for dementia is largely unknown. Recent studies revealed that epigenetic modifications may play a role in the pathogenesis of diabetes. We hypothesized that diabetes may cause epigenetic changes in the brain that may adversely affect synaptic function. We found significant elevation in the expression of histone deacetylases (HDACs) class IIa in the brains of diabetic subjects compared with control subjects, and these changes coincide with altered expression of synaptic proteins. In a mouse model of diet-induced type 2 diabetes (T2D), we found that, similar to humans, T2D mice also showed increased expression of HDAC IIa in the brain, and these alterations were associated with increased susceptibility to oligomeric Aβ-induced synaptic impairments in the hippocampal formation and eventually led to synaptic dysfunction. Pharmacological inhibition of HDAC IIa restored synaptic plasticity. Our study demonstrates that diabetes may induce epigenetic modifications affecting neuropathological mechanisms in the brain leading to increased susceptibility to insults associated with neurodegenerative or vascular impairments. Our study provides, for the first time, an epigenetic explanation for the increased risk of diabetic patients developing dementia.
authors.affiliation: Department of Neurology, Mount Sinai School of Medicine, New York, NY.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Bing
authors.initials: B
authors.lastname: Gong
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.forename: Cheuk
authors.initials: C
authors.lastname: Tang
authors.forename: Merina
authors.initials: M
authors.lastname: Varghese
authors.forename: Tuyen
authors.initials: T
authors.lastname: Nguyen
authors.forename: Weina
authors.initials: W
authors.lastname: Bi
authors.forename: Amanda
authors.initials: A
authors.lastname: Bilski
authors.forename: Shimul
authors.initials: S
authors.lastname: Begum
authors.forename: Prashant
authors.initials: P
authors.lastname: Vempati
authors.forename: Lindsay
authors.initials: L
authors.lastname: Knable
authors.forename: Lap
authors.initials: L
authors.lastname: Ho
authors.forename: Giulio M
authors.initials: GM
authors.lastname: Pasinetti
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism
chemical_list: D006655:Histone Deacetylases