Epigenetic mechanisms in Alzheimer's Disease: Therapeutic potential of Class specific HDAC inhibitors in insulin resistance induced cognitive impairments

Abstract

Numerous epidemiological studies have demonstrated that insulin resistance contributes to Alzheimer's disease (AD) pathogenesis. However the molecular mechanisms is still remain elusive but various studies have highlighted the epigenetic alterations and involvement of histone deacetylases (HDACs) in insulin resistance and cognitive deficits. In our previous study, we have explored the potential of pan HDAC inhibitor, SAHA, in high fat diet induced insulin resistance. In the present study, we have investigated the potential of isoform specific HDAC inhibitors in insulin resistance induced cognitive impairment in mice. Methods: Mice were subjected to either normal pellet diet (NPD) or high fat diet (HFD) for 8 weeks. HFD fed mice were treated with Class I specific HDAC inhibitor, CI-994 or Class II specific HDAC inhibitor, MC-1568 once daily for 2 weeks. Serum insulin, glucose, triglycerides, total cholesterol and HDL-cholesterol levels were measured. A battery of behavioural parameters was performed to assess cognitive functions. Results: HFD fed mice exhibit characteristic features of insulin resistance, showed a severe deficit in learning and memory. HFD feeding results in significant increase in Amyloid beta1-42 levels as compared with NPD fed mice In contrast, the mice treated with MC-1568 showed significant improvement in insulin resistance condition, marked decrease in Amyloid beta1-42 and significantly ameliorate the HFD induced decrease in BDNF and CREB level as compared to HFD group. Whereas, the mice treated with Class I HDAC inhibitor, CI-994 failed to show any improvement in insulin resistance and cognitive deficits. Conclusion: Based upon these results, it could be suggested that Class II HDAC inhibitors exert better neuroprotective effects as compared to Class I HDAC inhibitors associated with insulin resistant condition.