Alzheimer’s Disease (AD) is characterized by memory decline and neuronal pathology, including amyloid β (Aβ)plaques and oxidative stress. These markers are influenced by PARP1, which propagates cellular damage, and Sirt1, which protects against cellular damage. PARP1 becomes hyperactive in AD and inhibits Sirt1, thus propagating neuronal damage and memory decline. Direct PARP1 inhibition impairs vital cell functions and leads to drug resistance, indicating a need for new therapeutic targets to restore PARP1-Sirt1 balance.

We propose that histone macroH2A1.1 (mH2A1.1) is a master regulator of PARP1-Sirt1 balance because it inhibits PARP1 in various cell types, but a link between mH2A1.1 and Sirt1 is unknown. Based on our observation that mH2A1.1 declines in AD, Aim 1 will test the hypothesis that loss of mH2A1.1 inhibits Sirt1 activity by causing PARP1 to become hyperactive. Aim 2 will test the consequences of this inhibition for oxidative stress and pathology.

Experiments will be conducted in male and female 5xFAD AD model mice. We will manipulate mH2A1.1 and PARP1gene expression by delivering viral constructs directly into the hippocampus using stereotaxic surgery. mH2A1.1 will be depleted alone or in combination with PARP1 to assess their interaction in Sirt1 regulation. Effects on oxidative stress and Aβ pathology will be measured using commercially available assays and memory will be assessed using established tests of spatial and fear memory.

Our study will be the first to test a potential link between histone mH2A.1.1 and Sirt1. Preliminary evidence for loss of mH2A1.1 in AD indicates that reduction in this histone can trigger Sirt1 inhibition through PARP1 hyperactivity.PARP1 hyperactivity and loss of Sirt1 represent early pathological changes that propagate cellular damage and memory decline in AD. Thus, finding new ways to restore this pathway is critical for developing therapies for AD.

A key problem in AD treatment is the multifaceted pathology that affects all aspects of cell function. Instead of focusing on a single target, like Aβ, we focus on a chromatin factor that integrates multiple cellular signals and has the capacity to restore balance between vital regulators of neuronal health. mH2A1.1 has never been studied in relation to AD and characterizing its role in PARP1-Sirt1 regulation can open new directions for therapeutic intervention.