Epigenetic Mechanisms Linking Diabetes and Synaptic Impairments

• Published in: Diabetes (New York, N.Y.) Vol. 63; no. 2; pp. 645 - 654
• Main Authors: JUN WANG, BING GONG, KNABLE, Lindsay, LAP HO, PASINETTI, Giulio M, WEI ZHAO, CHEUK TANG, VARGHESE, Merina, TUYEN NGUYEN, WEINA BI, BILSKI, Amanda, BEGUM, Shimul, VEMPATI, Prashant
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.02.2014
• Subjects: Animals; Biological and medical sciences; Brain; Brain - cytology; Brain - metabolism; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diabetes research; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Epigenesis, Genetic - physiology; Epigenetic inheritance; Epigenetics; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Gene Expression Regulation - physiology; Genetic aspects; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Humans; Medical sciences; Mice; Mice, Inbred C57BL; Neurons - metabolism; Pathogenesis; Proteins; Rodents; Endocrinopathy; Epigenetics; Diabetes mellitus
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db13-1063

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.