The new roles of the autophagy-lysosomal pathway in spinal cord injury-mediated dementia

项目摘要 最近在治疗和管理方面的进步使许多遭受脊髓损伤(Sci)的患者得以存活。 在他们的创伤事件之后的许多年里。此外，考虑到老年人跌倒的增加，脊髓损伤的风险 在这些人口中一直在增加。最近的证据，包括大规模的纵向人口基础 研究表明，孤立的脊髓损伤(没有合并脑损伤)与以下因素相关的痴呆症的风险很高 严重的认知障碍。然而，关于脊髓损伤诱导的痴呆的机制或其机制还知之甚少 与发病年龄或阿尔茨海默病(AD)等与年龄相关的神经退行性疾病的关系。 这代表着一个未得到满足的医疗保健挑战。自噬-溶酶体途径是 胞内蛋白质和细胞器的降解及质量控制。自噬功能受损与 病理性蛋白质聚集，如磷酸-tau缠结和淀粉样蛋白斑块和 神经退行性疾病导致的神经细胞损伤和死亡。最近的数据表明， 自噬的扰动也可以改变炎症反应。因此，自噬-溶酶体的抑制 在年龄相关的AD/ADRD中，功能可能导致神经细胞损伤和炎症。 这项研究的目的是确定关键但基本上被忽视的大脑所涉及的关键机制 脊髓损伤后的变化并验证脊髓损伤加速抑制自噬-溶酶体功能的假说 大脑，最终促进脑神经退化和神经炎症，并导致痴呆症。 我们将使用年轻的成年自噬缺陷小鼠和老年动物来描述 自噬-溶酶体途径是脊髓损伤中脑部炎症和神经变性的关键调节因子。目标1 将确定进行性年龄相关的自噬-溶酶体功能紊乱是否在 脑在脊髓损伤后加速。对自噬通量、溶酶体功能、 炎症和神经退行性变将与痴呆样功能的特征相结合 检验慢性期脊髓损伤导致自噬加速抑制的假设的结果- 大脑中的溶酶体功能，导致神经炎症和神经退行性变 认知能力下降。目的2探讨年龄对脊髓损伤后自噬-溶酶体功能的影响。 中介的痴呆症。老龄C57BL/6小鼠遭受脊髓损伤将被用来研究年龄对脊髓损伤的影响 脊髓损伤介导的自噬-溶酶体功能失调，AD样神经病理，以及 大脑中的神经退化，以及相关的认知障碍。 由于我们目前的R01资助范围仅限于对自噬-溶酶体的短期评估 在急性脊髓损伤后损伤部位的功能，我们要求额外的资金来收集必要的长期数据 检验这一假设。我们希望利用这些数据来支持最终的R01应用，以进一步探索其作用 自噬-溶酶体功能在脊髓损伤与AD/痴呆之间的联系。

Project Summary Recent advances in treatment and management allow many patients suffering a spinal cord injury (SCI) to live for many years after their traumatic event. Moreover, given increased falls in the elderly, the risk of SCI has been increasing in that population. Recent evidence, including a large-scale longitudinal population-based study, indicates that isolated SCI (without concurrent brain injury) are at a high risk of dementia associated with substantial cognitive impairments. Yet little is known about the mechanisms of SCI-induced dementia or its relationship to age of onset or age-related neurodegenerative disorders such as Alzheimer’s disease (AD). This represents an unmet health-care challenge. The autophagy-lysosomal pathway is essential for intracellular protein and organelle degradation and quality control. Impaired autophagy is strongly implicated in accumulation of pathological protein aggregates such as phospho-tau tangles and amyloid  plaques and consequent neuronal cell damage and death in neurodegenerative diseases. Recent data indicate that perturbation of autophagy can also alter inflammatory responses. Thus, inhibition of autophagy-lysosomal function could contribute to both neuronal cell damage and inflammation observed in age-related AD/ADRD. The purpose of this study is to identify the key mechanisms involved in critical yet largely ignored brain changes after SCI and test the hypothesis that SCI accelerates inhibition of autophagy-lysosomal function in the brain, ultimately promoting brain neurodegeneration and neuroinflammation and leading to dementia. We will use young adult autophagy deficient mice and aged animals to delineate the roles of autophagy-lysosomal pathway as a key regulator of brain inflammation and neurodegeneration in SCI. Aim 1 will determine whether progressive age-related disruption of the autophagy-lysosomal function in the brain is accelerated following SCI. Multiple quantitative assessments of autophagy flux, lysosomal function, inflammation, and neurodegeneration will be combined with characterization of dementia-like functional outcomes to test the hypothesis that SCI at chronic phase leads to accelerated inhibition of autophagy- lysosomal function in the brain, contributing to neuroinflammation and neurodegeneration associated with cognitive decline. Aim 2 will determine the influence of age on the autophagy-lysosomal function in SCI- mediated dementia. Aged C57BL/6 mice subjected to SCI will be used to address the influence of age on SCI-mediated dysregulation of the autophagy-lysosomal function, AD-like neuropathology, and neurodegeneration in the brain, and associated cognitive impairments. Since the scope of our current R01 grant is limited to short-term assessment of autophagy-lysosomal function in the injury site after acute SCI, we request additional funds to collect long-term data necessary to test this hypothesis. We expect to use these data to support eventual R01 application to further probe the role of autophagy-lysosomal function in the link between SCI and AD/dementia.