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: 10369130
• 负责人: FRANCA CAMBI
• 金额: $ 15.41万
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10369130
• 关键词: Adult; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Axon; Behavior; Behavioral; Brain; Caliber; Cell Density; Cells; Cholesterol; Cognitive; Communities; DNA-Binding Proteins; Data; Disease; Electrophysiology (science); Energy Metabolism; Enzymes; Exploratory Behavior; Failure; Future; Genetic Transcription; Glutamates; Health; Hippocampal Formation; Hippocampus (Brain); Histologic; Human; Immunohistochemistry; Impaired cognition; 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 circuit; neural network; neuronal survival; neuroprotection; novel; novel strategies; protective effect; relating to nervous system; 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R 03应用旨在大大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（RD）。几条证据支持白色物质和OL损失在AD中的早期作用。 人类成像研究显示AD在明显认知下降和RNA Seq研究之前的白色物质变化 表明OL可能是最受影响的细胞类型，特别是在病程的早期。 AD.利用OL和髓鞘在AD/ADRD中的神经保护作用代表了一种阻止AD/ADRD的新策略。 在AD/ADRD过程的早期神经变性。我们计划利用我们的新的髓鞘增生FusOLcKO 运动和探索行为增强的小鼠。早期的研究表明大脑皮层神经退化 在脑损伤后， 计算机接口（BCI）探针植入年轻成年FusOLcKO小鼠。成人的终生髓鞘形成 大脑支持神经元网络的可塑性，这些可塑性是学习和维持认知健康的基础。与衰老 成人髓鞘形成的效率减弱，导致记忆力下降，在AD中，它在早期更快地失败， 病程。 这项提议旨在研究FUS依赖性髓鞘形成是否能防止神经变性， 通过维持神经网络增强神经元活性，改善衰老和AD/ADRD的记忆力 功能我们将使用定量结构和细胞分析来评估体内神经保护和动态 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度量来测量髓鞘形成过度对记忆编码的影响， 在年老的FusOL cKO小鼠中的巩固。最后，我们将建立一个新的小鼠系来研究神经保护作用。 通过将FusOLcKO与 一种人性化APP、AppNG-G-F线及执行装置 初步表型和组织学表征研究。这条新线代表了未来研究的资源 并将提供给AD科学界。 在完成这些研究后，我们预计 阐明了OL和髓磷脂在衰老认知强度中的保护作用，并产生了一种新的 AD髓鞘增生小鼠模型，作为未来研究髓鞘和OL在AD中作用的资源。