Grant: Project Grant

Alzheimer's disease (AD) is a devastating form of dementia characterized by memory loss and accumulation of amyloid beta plaques and tau tangles. Developing effective therapies relies on uncovering common mechanisms that underlie memory loss and AD pathology. Here, we will test the role of a newly identified memory suppressor, histone H2A.Z, as a key contributor to memory loss and AD pathology in several mouse models of AD. We recently discovered that H2A.Z impairs memory in normal mice and that levels of H2A.Z are increased in a mouse model of AD, suggesting that therapies aimed at inhibiting H2A.Z may reverse memory deficits. We will test this hypothesis using four approaches. First, we will use genome-wide sequencing to characterize AD-related changes in H2A.Z levels and distribution across the genome, allowing us to identify key genes and gene regions affected in AD. Next, we will determine if learning-induced changes in H2A.Z binding are impaired in mouse models of AD by quantifying 2 distinct histone pools that regulate stimulus-induced changes in H2A.Z. Third, we will test the efficacy of H2A.Z and the proteins that regulate its binding for treating memory loss and pathology in mouse models of AD. We will use virally-mediated approaches to deplete genes encoding H2A.Z, or the H2A.Z-regulating proteins Anp32E and Scrap. Finally, we will validate H2A.Z as a target in human AD brains, and use human cell lines to directly test the ability of H2A.Z to reverse AD pathology. The use of multiple H2A.Z regulators allows us to test several promising new targets as potential AD therapies, with the potential to simultaneously reverse memory deficits and the underlying plaques and tangles through a novel category of histone proteins.