Principal Investigator Li-Huei Tsai
Among the available AD mouse models, the CK-p25 mouse uniquely recapitulates the profound neuronal loss that is observed in advanced stages of AD. Thus, we used this model to explore novel therapeutic approaches that may be beneficial for cognition even after profound synaptic loss and neuronal death have occurred. We show that treating CK-p25 mice with chemical histone deacetylase (HDAC) inhibitors induces robust synaptogenesis and dendritic growth, restores learning, and recovers long-term memory—even after massive neuronal loss has occurred. These findings demonstrate that an epigenetic mechanism involving increased histone acetylation and chromatin remodeling can be beneficial for learning and memory, and that these manipulations are effective even in the face of neuronal loss and neurodegeneration. These observations suggest that memory is not completely erased after neurodegeneration, and provide compelling evidence for developing HDAC inhibitors to reverse cognitive impairment in Alzheimer’s disease.
Specifically, our work has shown that the inhibition of HDAC2 by HDAC inhibitors is beneficial to learning and memory in both normal mice and in mouse models of neurodegeneration. We find that HDAC2 levels are increased in mouse AD models of as well as in postmortem brain samples from AD patients. More importantly, we show that the normalization of HDAC2 levels in mouse models of AD restores cognitive function, even following severe neurodegeneration. These findings advocate for the development of selective inhibitors of HDAC2 and suggest that cognitive capacities following neurodegeneration are not entirely lost, but merely impaired by this epigenetic blockade. Our current work is directed towards better understanding the HDAC2-corepressor complexes that are relevant to memory and which may be altered in AD.
To better understand the changes in the epigenome during neurodegeneration, we performed RNA- and chromatin immunoprecipitation (ChIP)-sequencing in the hippocampi of CK-p25 mice using seven different chromatin marks specific for active and inactive regulatory elements and gene bodies. We found that neuronal genes, those involved in synaptic transmission and learning/memory, are significantly downregulated, while innate and adaptive immune response genes are massively upregulated in the brains of CK-p25 mice. Notably, the direction of gene expression changes in the CK-p25 mice is remarkably similar to that observed in profiling studies conducted in the human AD hippocampus. From human data in which we examined genome regions orthologous to those containing disease-associated changes in enhancer elements in the mouse CK-p25 brain, we have identified master regulators of many genes that change expression in AD. Finally, we found that AD-associated genetic variants are enriched in the increased enhancer orthologs with a specific consistent temporal profile, and depleted in the decreased activity orthologs, implicating that alterations in the regulation of immune genes may underlie AD predisposition, while changes in neural pathways represent non-genetic effects. Currently, we are performing cell type specific epigenomic analysis and single cell RNA-sequencing in mouse and human brains to further understand the roles of different neural cell types including neurons, astrocytes, and microglia in AD-related neurodegeneration.