Sex‐specific accumulation and therapeutic effect of the histone variant H2A.Z in Alzheimer’s disease

Abstract Background There is growing evidence that dysregulation of gene expression plays a role in cognitive deficits and neuropathology in Alzheimer’s disease (AD), thus prompting interest in epigenetic factors as mechanisms of neurodegeneration and memory loss. Here, we assess the therapeutic potential of the histone variant H2A.Z. H2A.Z is a memory suppressor that is actively removed from DNA during learning to promote gene expression and memory formation. The memory‐suppressive effects of H2A.Z are further supported by our finding that H2A.Z levels increase in the aged brain and may act as a prelude to age‐related memory decline. We hypothesize that H2A.Z also accumulates in AD and that targeted depletion of H2A.Z is an effective therapy for memory impairment. Methods To characterize H2A.Z levels in the AD brain, we assessed genome wide (ChIP‐seq) and site‐specific (ChIP‐qPCR) binding of H2A.Z to DNA as well as mRNA expression of genes encoding H2A.Z in both the human post‐mortem and 5xFAD mouse hippocampus. To directly test the therapeutic potential of H2A.Z depletion, adeno‐associated virus (AAV) vector containing short hairpin RNA against H2A.Z was delivered in the hippocampus of 5xFAD mice and memory was assessed using object location and contextual fear conditioning tasks. Results Consistent with the hypothesis that H2A.Z accumulates in the AD brain, binding of H2A.Z increased at several memory and AD‐related genes in the human and 5xFAD female hippocampus. Interestingly, this effect was sex specific, as H2A.Z binding decreased in the male hippocampus across species. Similarly, mRNA expression of genes encoding H2A.Z increased in the human and 5xFAD female hippocampus. This female‐specific increase in H2A.Z was paralleled by the remediation of memory impairment following H2A.Z depletion in 5xFAD females but not males. Conclusion Our data are the first demonstration of histone variants as regulators of AD‐related memory impairment. The sex‐specific changes in H2A.Z generalize across species and provide promising support for H2A.Z depletion as a therapeutic strategy for AD in females.