Epigenetic Mechanisms Linking Diabetes and Synaptic Impairments
- Jun Wang1,2,
- Bing Gong1,
- Wei Zhao1,
- Cheuk Tang3,
- Merina Varghese1,
- Tuyen Nguyen3,
- Weina Bi1,
- Amanda Bilski1,
- Shimul Begum1,
- Prashant Vempati1,
- Lindsay Knable1,
- Lap Ho1 and
- Giulio M. Pasinetti1,2⇑
- 1Department of Neurology, Mount Sinai School of Medicine, New York, NY
- 2Geriatric Research, Education and Clinical Center, James J. Peters Veterans Affairs Medical Center, Bronx, NY
- 3Department of Radiology, Mount Sinai School of Medicine, New York, NY
- Corresponding author: Giulio M. Pasinetti, .
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.
- Received July 5, 2013.
- Accepted October 15, 2013.
- © 2014 by the American Diabetes Association.
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