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

衰老和 AD 中的认知能力下降：FusOLcKO 髓鞘形成过多的神经保护作用

• 批准号: 10549814
• 负责人: FRANCA CAMBI
• 金额: $ 15.52万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10549814
• 关键词: Adult; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Axon; Behavior; Behavioral; Brain; Cell Density; Cells; Cholesterol; Cognitive; Communities; DNA-Binding Proteins; Data; Diameter; Disease; Electrophysiology (science); Energy Metabolism; Enzymes; Exploratory Behavior; Failure; Future; Genetic Transcription; Glutamates; Health; Hippocampal Formation; Hippocampus; Histologic; Human; Immunohistochemistry; Impaired cognition; Injury; Learning; Life; Maintenance; Measures; Memory; Memory Loss; Metabolic stress; Mus; Myelin; Nerve Degeneration; Neurons; Neurophysiology - biologic function; Nuclear RNA; Oligodendroglia; Pathology; Phenotype; Phosphorylation; Play; RNA Processing; RNA Splicing; Resources; Role; Signal Transduction; Standardization; Structure; Synapses; Testing; Thick; age related; aged; brain computer interface; cell type; cholesterol biosynthesis; density; fused in sarcoma; imaging study; implantation; improved; in vivo; memory consolidation; memory encoding; motor behavior; mouse model; myelination; neural; neural circuit; neural network; neuronal survival; neuroprotection; novel; novel strategies; protective effect; resilience; response; spatial memory; synaptogenesis; transcriptome sequencing; visual learning; white matter; white matter change; young adult

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.

该 R03 应用旨在极大地提高对少突胶质细胞和髓磷脂支持的理解 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）。多项证据支持白质和 OL 损失在 AD 中的早期作用。 人类影像学研究表明，在明显的认知能力下降之前，AD 患者的白质发生了变化，RNA 测序研究也显示了这一点 证明 OL 可能是受影响最严重的细胞类型，尤其是在早期 广告。利用 OL 和髓磷脂对 AD/ADRD 的神经保护作用代表了一种阻止 AD/ADRD 的新策略 AD/ADRD 病程早期的神经退行性变。我们计划利用我们的新型髓鞘过度形成 FusOLcKO 小鼠表现出增强的运动和探索行为。早期研究表明皮质神经变性 大脑后 FusOLcKO 的记忆编码区域的神经元活动减少且神经元活动增强 将计算机接口 (BCI) 探针植入年轻成年 FusOLcKO 小鼠中。成人终生髓鞘形成 大脑支持神经元网络的可塑性，是学习和维持认知健康的基础。随着老化 成人髓鞘形成的效率减弱，导致记忆力下降，在 AD 中，髓鞘形成速度更快、更早失效。 病程。 该提案旨在调查 FUS 依赖性髓鞘形成过度是否可以预防神经退行性变， 通过维持神经网络增强神经元活动并改善衰老和 AD/ADRD 中的记忆力 功能。我们将使用定量结构和细胞分析来评估神经保护和体内动态 电生理学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 以及适应性髓鞘形成的指标，以测量髓鞘形成过度对记忆编码和记忆编码的影响 老年 FusOL cKO 小鼠的巩固。最后，我们将生成一个新的小鼠品系来研究神经保护作用 FusOLcKO 与 AD 杂交对髓鞘过度形成的影响 人性化APP，AppNG-G-F连线并执行 初始表型和组织学特征研究。这条新线代表了未来研究的资源 并将提供给 AD 科学界。 完成这些研究后，我们期望 阐明了 OL 和髓磷脂对衰老认知强度的保护作用，并产生了一种新的 AD 高髓鞘形成小鼠模型可作为未来研究髓磷脂和 OL 在 AD 中的作用的资源。