Alzheimer's disease (AD) is the most common neurodegenerative disorder associated with dementia and, while other major causes of death have declined in the past ten years, the incidence of AD has risen alarmingly. In a mouse model of AD-like neurodegeneration, the CK-p25 mouse, we showed that alterations in chromatin remodeling, via the inhibition of histone deacetylase (HDAC) activity, ameliorated synaptic and cognitive impairments. Moreover, we found that the enhancement of cognitive function specifically required inhibition of the class I histone deacetylase, HDAC2, which plays a critical role in cognition by binding to the regulatory elements of genes implicated in synaptic plasticity and memory formation. Our preliminary data show that HDAC2 expression is induced upon neurotoxic stimulation, including A?42 and H2O2 treatments. Importantly, in postmortem human AD brains and in AD mouse models, HDAC2 shows a marked upregulation, which is accompanied by increased association of HDAC2 with memory genes and the drastic reduction in the expression of these genes. We propose to examine the mechanism underlying the HDAC2-mediated inhibition of plasticity genes in human induced pluripotent stem cell (iPSC)-derived neurons derived from control individuals as well as both familial and sporadic AD patients. We will examine the expression of HDAC2 mRNA and protein in these iPSC-derived neurons, and will PCR-sequence each sporadic AD line for the APOE genotype. We will then expose these neurons to neurotoxic stimuli, and will examine the epigenetic alterations in the control, familial, and sporadic AD neurons by conducting chromatin immunoprecipitation with antibodies against HDAC2, followed by Illumina second-generation sequencing. We will also examine changes in the transcriptome of these iPSC-derived neurons, with and without neurotoxic stimuli, by conducting RNA sequencing. The proposed studies will test the hypothesis that neurons derived from familial or sporadic AD patients are more susceptible to neurotoxic insults than those from controls, and that this heightened sensitivity results in an increased suppression of neural plasticity genes by HDAC2 upregulation. Importantly, we will also examine the effects of shRNA-mediated HDAC2 knockdown, as well as treatment with several HDAC inhibitor compounds, both known and novel, upon the HDAC2-mediated alterations in learning and memory gene expression in control, familial, and sporadic AD neurons with and without neurotoxic stimulation. The experiments outlined in this application will test the role of epigenetic alteration as a novel mechanism underlying AD-associated cognitive decline.
We have previously shown that class I histone deacetylase, HDAC2, responds to neurotoxicity by binding to the promoters, and suppressing the expression, of genes critical to normal learning and memory. The current proposal will use human neurons derived from patient induced pluripotent stem cells to test the hypothesis that neurons from Alzheimer's disease patients are more susceptible to neurotoxicity-induced chromatin remodeling via HDAC2.
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