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.

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 维持老化和阿尔茨海默氏病（AD）/AD中的轴突完整性，突触和神经网络功能 相关痴呆症（RD）。 人类的成像研究表明，在明显的认知和RNA SEQ研究之前，AD的白质变化 证明OLS可能是最严重影响的细胞类型，尤其是在早期 AD。 在AD/ADRD的早期，神经变性。 显示增强电机和探索性的老鼠 减少并在大脑后的Fusolcko的记忆中增强了神经元活性 年轻的成人小鼠的计算机界面（BCI）探针植入。 大脑支持神经元网络的塑料，以衰老的认知健康学习和维护。 成人神秘性的功效削弱了记忆力下降和广告中的广告中的功效 疾病的病程。 该建议旨在调查FUS依赖性过度屈服是否可以防止神经变性， 通过维护神经网络增强神经元活动并改善记忆/AD/ADRD 功能。 电生理记录评估神经网络活动。 以及适应性髓鞘化的指标，以测量过度分泌对记忆编码和的影响 老化的FUSOL CKO小鼠的安装。 通过将fusolcko与AD中的过度分泌作用 人性化应用程序，AppNG-G-F线并执行 最初的表型和组织学特征研究代表了未来研究的资源 并将提供给广告科学界。 在压缩研究时，我们希望 阐明了OL和髓磷脂在认知强度IND中的保护作用，从而产生了一种新颖 AD超元素穆斯尔（Mousel）充当了关于髓磷脂和AD作用的Aresource未来研究。