Dissecting the neuroprotective role of an RNA binding protein in neurodegeneration

Project Summary / Abstract AD-related dementia (ADRD) are devastating brain diseases with unmet medical needs. Abnormal aggregations of amyloid-like proteins such as Aβ and tau proteins are pathologic hallmarks. The FDA granted accelerated approval to the anti-amyloid drugs aducanumab and lecanemab, signifying the potential of amyloid- lowering strategies in AD drug development. While the detrimental effects of amyloid aggregations are well- documented, the current challenge lies in identifying risk factors that directly or indirectly influence the accumulation of these proteins in the nervous system. Notably, recent studies have identified a group of RNA binding proteins (RBPs) with significant protective effects against neurodegeneration. However, the molecular functions of these newly identified neuroprotective genes in AD pathophysiology remain unexplored. Therefore, it is imperative to elucidate the molecular mechanisms by which these RBPs mitigate AD-related cellular dysfunction. Our long-term goal is to design innovative interventions to prevent and treat brain abnormality in neurodegenerative disorders including AD. Our group has previously revealed critical molecular regulators implicated in AD. We have identified an RBP, RBM8A that is significantly downregulated in human postmortem AD brains and consistently reduced in 5XFAD mouse brains. Intriguingly, our preliminary data have shown that increased dosages of RBM8A at different ages alleviate Aβ amyloid formation in 5XFAD mice. Our objectives are to examine how different gene dosages of RBM8A affect pathological and behavioral changes in 5XFAD mouse and to identify targets most relevant for RBM8A-dependent neuronal protective effects. Our rationale for this project is that its successful completion would provide a robust, evidence-based framework for developing therapeutic strategies for AD or other neurodegenerative diseases. To achieve our objectives, we will rigorously test two Specific Aims: 1) Determine the role of Rbm8a in AD pathological and behavioral changes in 5XFAD mouse model; and 2) Determine molecular targets of RBM8A during neurodegeneration in 5XFAD mouse brains. It is anticipated that the proposed studies will provide the underlying mechanism(s) by which RBM8A modulates neurodegeneration in AD. What is learned here will be utilized to identify cell type-specific, phenotype-relevant mRNA targets that can serve as novel drug targets for AD patients. The successful completion of the proposed studies would have an important positive impact on developing therapies to prevent and/or treat patients at risk for AD or other neurodegenerative diseases.