Class 1 HDACs Modulate Synapse‐Related Genes in Mouse Models of Aging and Alzheimer’s Disease
Bryan McClarty, Guadalupe Rodriguez, Hongxin Dong- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
Studies have demonstrated that epigenetics plays an important role in both aging and Alzheimer’s disease (AD) pathogenesis, however, whether epigenetic dysregulation during aging can initiate AD development and/or exacerbate AD progression remains unclear. Given aging is the major risk factor of AD, it is critical to determine the epigenetic alterations occurring during aging and how these changes influence AD pathogenesis.
Methods
In this study, 3, 12, and 18‐month‐old APP/PS1 mice and WT littermates were used for a series of behavioral tests to evaluate and compare different memory domains, including recognition, short‐term working, and long‐term spatial reference memory in aging and AD progression. After behavioral testing, the hippocampus and prefrontal cortex (PFC) were collected for biochemical assessment to determine the dynamic changes of class 1 HDACs globally and at gene promoters that are associated with synaptic structure and function, namely Nr2a, GluR1 Glur2, and Psd95. Additionally, synaptic gene expression and H3K9ac levels at the gene promoters were evaluated during aging and AD progression.
Results
Our results showed that recognition and short‐term working memory declined in WT mice only at 18 months of age, but significantly declined in the three memory domains of APP/PS1 mice at both 12 and 18 months of age. Moreover, 18 months of age APP/PS1 mice showed exacerbated recognition and spatial working memory deficits. We also found HDACs modulate the synaptic‐related genes in a genotype and regional manner. More specifically, HDAC 2 modulated synaptic gene expression through dysregulations of H3K9ac levels at the gene promoters in the hippocampus during aging and AD progression. While HDAC 3 modulated synaptic gene expression through dysregulations of H3K9ac levels at gene promoters in the prefrontal cortex during AD progression. The dynamic changes of HDACs and H3K9ac levels during aging and AD progression are associated with specific declines in memory.
Conclusion
Our findings suggest a potential differential HDAC modulation of synaptic gene expression in aging and AD progression, which impacts the decline of different memory domains. Future work will confirm our findings and will begin using genetic manipulation approaches to dissect individual class 1 HDAC contributions to aging and/or AD progression in the hippocampus and PFC.