Class 1 histone deacetylases differentially modulate memory and synaptic genes in a spatial and temporal manner in aged and APP/PS1 mice

Epigenetics plays a vital role in aging and Alzheimer's disease (AD); however, whether epigenetic alterations during aging can initiate AD and exacerbate AD progression remains unclear. In this study, 3-, 12- and 18- month-old APP/PS1 mice and WT littermates underwent memory tests, then synapse-related gene expression, class 1 histone deacetylases (HDACs) abundance, and H3K9ac levels at target gene promoters, were evaluated in the hippocampus and prefrontal cortex (PFC). Our results showed recognition and long-term spatial memory impaired in 18-month-old WT mice and recognition, short-term working, and long-term spatial reference memory deficits in 12-and 18- month-old APP/PS1 mice. The memory impairments are associated with synapse-related gene nr2a, glur1, glur2, psd95 expression, HDAC abundance, and H3K9ac regulation. More specifically, HDAC 2 modulated synapse-related gene expression through H3K9ac at the gene promoters during aging and AD progression in the hippocampus. Conversely, HDAC 3 modulated synapse-related gene expression through H3K9ac at the gene promoters during AD progression in the PFC. These findings suggest a differential HDAC modulation of synapse-related gene expression in aging and AD.