The Therapeutic Potential of HDAC Inhibitors for Dopamine Deficiency in Alzheimer’s Disease: A Research Protocol

Abstract

Introduction: Histone deacetylases (HDACs) are enzymes with epigenetic down-regulatory functions that are linked to the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease. Dopamine deficiency in the ventral tegmental area (VTA) is associated with memory deficits characteristic of Alzheimer’s disease. HDAC inhibitors (HDACi) may counter HDAC downregulation of dopamine, increasing VTA dopamine. This investigation hypothesizes that HDACi can increase net VTA dopamine concentration and thus improve memory in Tg2576 transgenic mice models of Alzheimer’s disease. Methods: Firstly, a promoter for each of the 18 HDACs will be individually delivered into mice VTA to identify those decreasing local dopamine concentrations, which will be measured using microdialysis and a Paired-Samples T-Test. Secondly, an HDACi corresponding to each HDAC will be selected and longitudinally injected into the mice while measuring VTA dopamine concentration using microdialysis and a Paired-Samples T-Test to indicate the HDACi countering HDAC-induced dopamine downregulation. Lastly, the dopamine receptor antagonist flupentixol will be injected into the VTA as mice undertake the Novel Object Recognition Test. Performance will indicate whether HDACi-induced increases in VTA dopamine improve memory and learning function. Results: Lower post-measurement scores are expected for HDACs that decrease VTA dopamine concentration relative to baseline means. Greater post-measurement scores are expected for HDACi that increase VTA dopamine concentration relative to pre-measurement scores. The lowest mean exploration times are expected for HDAC delivery, then HDACi injection with flupentixol, no treatment, and finally HDACi alone. Tg2576 mice are expected to have lower mean exploration times than healthy B6.SJL mice. Discussion: The first two experiments identify HDACs that decrease net VTA dopamine concentration and HDACi that increase it through Paired-Samples T-Tests. The final experiment investigates whether dopamine rehabilitation caused by HDACi can produce tangible memory improvements. A two-way ANOVA test will determine if exploration times between the four treatment groups are statistically significant, concluding whether learning and memory improved by manipulations alone. Conclusion: The memory and learning of Tg2576 Alzheimer’s mice models are expected to improve through the inhibition of dopamine-decreasing HDACs in the VTA. This protocol offers a preliminary strategy towards identifying the HDACs and HDACi relevant to dopamine deficiency in Alzheimer’s disease.