This R03 application aims to greatly improve understanding of oligodendrocytes and myelin support in maintaining axonal integrity, synapse and neural network function in aging and Alzheimer’s disease (AD)/AD Related Dementias (RD). Several lines of evidence support the early role of white matter and OL loss in AD. Imaging studies in humans show white matter changes in AD before overt cognitive decline and RNA Seq studies demonstrated that OLs are perhaps the most substantially impacted cell-type especially early in the course of AD. Harnessing the neuroprotective effects of OL and myelin in AD/ADRD represents a novel strategy to halt neurodegeneration early in the course of AD/ADRD. We plan to leverage our novel hypermyelinating FusOLcKO mice that show enhanced motor and exploratory behavior. Early studies suggest that cortical neurodegeneration is reduced and neuronal activity is enhanced in memory encoding regions of the FusOLcKO following brain computer interface (BCI) probe implantation in young adult FusOLcKO mice. Lifelong myelination in the adult brain supports neuronal networks plasticity underlying learning and maintenance of cognitive health. With aging the efficiency of adult myelination weakens leading to memory decline and in AD it fails faster and early in the course of the disease. This proposal aims to investigate if FUS dependent hypermyelination protects against neurodegeneration, enhances neuronal activity and improves memory in aging and AD/ADRD by maintaining neural network function. We will use quantitative structural and cellular analyses to assess neuroprotection and dynamic in vivo electrophysiology recording to assess neural network activity. We will use standardized spatial memory testing and metrics of adaptive myelination to measure the effect of hypermyelination on memory encoding and consolidation in aged FusOL cKO mice. Finally, we will generate a new mouse line to study the neuroprotective effect of hypermyelination in AD by crossing the FusOLcKO with the humanized APP, AppNG-G-F line and perform initial phenotypic and histological characterization studies. This new line represents a resource for future studies and will be made available to the AD scientific community. At completion of these studies, we expect to have elucidated the protective effect of OL and myelin in cognitive strength in aging and to have generated a novel AD hypermyelinating mouse model to serve as a resource for future studies on the role of myelin and OL in AD.