Leveraging ΔFosB as a potential therapeutic for Alzheimer's Disease

PROJECT SUMMARY There is an urgent need to develop effective strategies to combat memory impairments and cognitive decline in Alzheimer’s disease (AD), but there is a serious lack of validated drug targets. Our team recently demonstrated that the transcription factor FosB accumulates in the hippocampus, a brain region critical for learning, in AD patients and AD mouse models. FosB regulates the expression of genes crucial for memory and learning, and its accumulation in hippocampus drives cognitive deficits. We recently also demonstrated that FosB binds DNA under control of a redox switch. This is intriguing because AD generates tremendous oxidative stress in the brain. The exact pathological species of FosB that accumulates in AD is not known, i.e., whether the protein is oxidized and which of its binding partners are preferred. It is also not known exactly how the redox switch works and how it could be targeted with small molecules. We do know that FosB has a well- described role in drug addiction, accumulating in the nucleus accumbens, where it mediates the rewarding effects of drugs of abuse by regulating the expression of many genes crucial to drug addiction. Through our parent grant, we are developing chemical probes to investigate the mechanism of FosB in vivo and validate it as a potential drug target to treat addiction. Our new findings suggest that FosB can also be leveraged to counter cognitive decline in AD and serve as a biomarker to diagnose or predict early onset AD. We hypothesize that the FosB redox switch and dimerization partner can be leveraged to render FosB ‘druggable’, enabling the design of compounds that bind FosB: 1) with high affinity, 2) with selectivity, and 3) that regulate FosB function in a tunable manner (e.g., positively or negatively). Building on our success in targeting FosB with compounds in our parent NIDA grant, we propose in this Administrative Supplement to gather key preliminary data that can be used to validate FosB as a biomarker and therapeutic target for AD. Our approach is to: 1) delineate the pathological species of FosB that accumulate in AD mice; 2) delineate the mechanism of the redox switch through structure-based mutagenesis so that we can leverage its features to design selective probes; and 3) identify a panel of novel compounds which selectively target the redox switch of FosB using a newly designed cell-based assay. To this end, we already have a very strong, translational research platform in place that draws on our prior work using animal models of cognition, an AD mouse model, biochemical assays, medicinal chemistry, and structural biology. Thus, the positive impact will be to determine the AD-relevant species of FosB and to develop strategies to rationally target them to counteract cognitive impairment in AD. This proposal is also innovative because it develops a new AD animal model and identifies novel, strategic chemical probes and critical mechanistic insight on the path towards developing molecules that target FosB as novel therapeutics or diagnostics for cognitive decline in AD.