Cognitive decline in aging and AD: neuroprotection by hypermyelination in FusOLcKO

此R03应用程序旨在极大地提高对少突胶质细胞和髓鞘支持的理解。 在衰老和阿尔茨海默病(AD)/AD中维持轴突完整性、突触和神经网络功能 相关痴呆症(RD)。有几条证据支持白质和OL丢失在AD中的早期作用。 人类成像研究显示阿尔茨海默病患者认知功能明显下降前脑白质的变化 证明OL可能是受影响最大的细胞类型，特别是在 广告。利用OL和髓鞘对AD/ADRD的神经保护作用是一种新的止血策略 AD/ADRD病程早期神经退行性变。我们计划利用我们的新型超髓鞘FusOLcKO 表现出增强的运动和探索行为的小鼠。早期研究表明，皮质神经退行性变 脑后FusOLcKO记忆编码区神经元活性增强 计算机接口(BCI)探针植入幼年FusOLcKO小鼠。成人的终生髓鞘形成 大脑支持神经网络的可塑性，是学习和维持认知健康的基础。随着年龄的增长 成人髓鞘形成的效率减弱，导致记忆力下降，在AD患者中，髓鞘形成的速度更快，早期 疾病的病程。 这项建议旨在研究依赖FUS的超髓鞘形成是否可以防止神经退化， 通过维持神经网络增强衰老和AD/ADRD中的神经元活性和改善记忆 功能。我们将使用定量的结构和细胞分析来评估体内的神经保护和动态 电生理记录以评估神经网络活动。我们将使用标准化的空间记忆测试 和适应性髓鞘形成的指标，以衡量超髓鞘形成对记忆编码和 老龄FusOL CKO小鼠的固结。最后，我们将产生一种新的小鼠系来研究神经保护 FusolcKO与FusolcKO杂交对阿尔茨海默病患者髓鞘形成的影响 人性化APP，AppNG-G-F线和表演 最初的表型和组织特征研究。这条新的线代表了未来研究的资源 并将提供给AD科学界。 在这些研究完成后，我们预计会有 阐明了OL和髓鞘在衰老过程中对认知能力的保护作用，并产生了一种新的 AD多髓鞘小鼠模型作为未来研究髓鞘和OL在AD中的作用的资源。

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.