PROJECT SUMMARY Alzheimer’s disease (AD) is an age-related neurodegenerative disorder that causes memory loss and cognitive decline. Synaptic dysfunction and loss correlates strongly with cognitive impairment in AD. Aging is the leading risk factor for AD, and epigenetic mechanisms involving histone deacetylases (HDACs) play an important role in aging and age-related neurodegenerative disorders. Among the 11 zinc-dependent HDACs, HDAC9 is the most abundant isoform in the brain, found exclusively in neurons. We provide key preliminary data showing that HDAC9 expression in the hippocampus and prefrontal cortex (PFC) diminishes with aging in wild-type mice, and that reduced HDAC9 expression precedes the onset of amyloid deposition in the APP/PS1 mouse model of AD. Consistent with these preclinical findings, AD patients exhibited decreased HDAC9 expression in the dorsolateral PFC. Moreover, global or hippocampal CA1-specific deletion of HDAC9 induces cognitive impairment and impairs synaptic plasticity, while HDAC9 overexpression produces cognitive-enhancing effects. We hypothesize that reduced neuronal HDAC9 mediates cognitive decline, synaptic dysfunction and other neuropathologies associated with brain aging and AD. To test this hypothesis, we propose three specific aims. In Aim 1, we will test the hypothesis that loss of HDAC9 in hippocampal and PFC neurons mediates age- and AD-related neuropathology and cognitive impairment. In Aim 2, we will test the hypothesis that the histone methyltransferase EZH2 [the catalytic component of the polycomb repressive complex 2 (PRC2), which catalyzes repressive H3K27me3 modifications at gene promoters] epigenetically silences HDAC9 expression in the hippocampus and PFC during aging and in AD. In Aim 3, we will test the hypothesis that neuronal pentraxin 2 (NP2), nerve growth factor inducible (VGF), and brain-derived neurotrophic factor (BDNF) mediate the downstream effects of HDAC9 on hippocampal synaptic plasticity and cognition. We expect that the results will provide insight into molecular mechanisms underlying the epigenetic control of genes related to aging and AD and offer potential targets for future therapeutic interventions.

PROJECT NARRATIVE Alzheimer’s disease (AD) is the most common neurodegenerative disorder, currently accounting for 60–80 % of dementia cases. This application aims at identifying the molecular bases underlying the effects of aging on AD-related neuropathology and cognitive deficits. We expect that the results will provide insights into therapeutic interventions targeting specific HDACs and tissue-selective therapy.