Project Summary Alzheimer’s disease (AD) is highly polygenic and much of its genetic architecture remains poorly understood. Our current knowledge of AD molecular pathogenesis was mostly derived from studies of familial mutations of early-onset AD. Near complete understanding of AD pathogenic mechanisms requires thorough investigation of the still highly heritable late-onset AD (LOAD) and determination of disease relevant mechanisms. RNA binding proteins (RBP) have emerged frequently involved in AD and AD associated dementia (ADRD). Mutations in RBPs cause frontotemporal dementia. Dysfunction of RBPs and RNA processing are increasingly implicated in pathology and progression of AD/ADRD. However, little is known about RBPs’ contributions to AD. We have been studying the role of RNA binding protein PTBP2 in the brain for 14 years. This application is built on our parental R01 award (R01NS104041) to extend our analyses of PTBP2 in the context of Alzheimer’s Disease. Funded by the parental R01 award, our published works have demonstrated the essential roles of PTBP2 and its regulatory targets in axonogenesis. Guided by our ongoing research and unpublished data, we hypothesize that PTBP2 deficiency accelerates Alzheimer’s disease progression. To investigate the PTBP2’s contribution to AD progression, we have started breeding Ptbp2 heterozygous mice with 5xFAD mice expressing five AD familial mutations. We will determine whether PTBP2 deficiency accelerates or exacerbates early manifestations of AD pathology. We will also develop resources including aged compound mutants for studies of late-stage AD pathology. Our long history of researching PTBP2 in the brain places us in a unique position to evaluate this hypothesis. The proposed research will be the prelude to understanding the interactions between PTBP2, familial AD mutations, and other AD risk variants in AD progression.