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

自噬-溶酶体途径在脊髓损伤介导的痴呆中的新作用

• 批准号: 10114910
• 负责人: Junfang Wu
• 金额: $ 33.75万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10114910
• 关键词: Acute; Address; Affect; Age; Age of Onset; Aging; Alzheimer' s Disease; Amyloid beta-Protein; Animals; Anti-Inflammatory Agents; Autophagocytosis; Behavior; Brain; Brain Injuries; Brain region; C-terminal; C57BL/6 Mouse; Cell Death; Cell Differentiation process; Cells; Chronic; Chronic Phase; Data; Defect; Dementia; Elderly; Encephalitis; Female; Funding; Genes; Grant; Healthcare; Impaired cognition; Impairment; Inflammation; Inflammatory; Inflammatory Response; Injury; Link; Mediating; Memory Loss; Mental Depression; Modeling; Motor; Mus; Nerve Degeneration; Nervous System Physiology; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurologic Dysfunctions; Neurons; Neuropsychology; Organelles; Pathologic; Pathway interactions; Patients; Phenotype; Physiological; Pilot Projects; Population; Population Study; Proteins; Quality Control; Rattus; Research; Risk; Role; Senile Plaques; Site; Spinal cord injury; Testing; Time; age related; age related neurodegeneration; aged; aging brain; base; cell injury; cognitive development; dementia risk; endoplasmic reticulum stress; experimental study; falls; functional outcomes; high risk; inhibition of autophagy; injured; male; neuroinflammation; neuropathology; progressive neurodegeneration; protein aggregation; proteostasis; tau-1; traumatic event; young adult

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.

项目摘要 治疗和管理的最新进展使许多患有脊髓损伤（SCI）的患者得以生存 在他们的创伤事件发生后的许多年里。此外，考虑到老年人福尔斯跌倒的增加， 在这个人口中不断增加。最近的证据，包括大规模的纵向人口为基础的 一项研究表明，孤立的SCI（没有并发脑损伤）是与痴呆症相关的高风险， 严重的认知障碍然而，关于SCI诱发痴呆的机制或其 与发病年龄或年龄相关的神经退行性疾病如阿尔茨海默病（AD）的关系。 这是一个尚未解决的保健挑战。自噬-溶酶体途径对于 细胞内蛋白质和细胞器降解和质量控制。受损的自噬与 病理性蛋白质聚集体如磷酸化-tau缠结和淀粉样蛋白斑块的积累， 从而导致神经变性疾病中的神经元细胞损伤和死亡。最近的数据显示， 自噬的扰动也可以改变炎症反应。因此，抑制自噬-溶酶体 功能可能有助于在年龄相关AD/ADRD中观察到的神经元细胞损伤和炎症。 这项研究的目的是确定关键的，但在很大程度上被忽视的大脑参与的关键机制， SCI后的变化，并测试SCI加速自噬溶酶体功能抑制的假设， 大脑，最终促进大脑神经变性和神经炎症，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SCI中脑炎症和神经变性的关键调节因子。要求1 将确定是否进行性的年龄相关的自噬溶酶体功能的破坏， 大脑在SCI后加速。对自噬通量、溶酶体功能、 炎症和神经变性将与痴呆样功能性痴呆的表征相结合， 结果，以检验SCI在慢性期导致自噬加速抑制的假设- 脑中的溶酶体功能，导致与神经炎性反应相关的神经炎症和神经变性。 认知能力下降目的2将确定年龄对SCI中自噬-溶酶体功能的影响。 介导的痴呆症。将使用经历SCI的老龄C57 BL/6小鼠来解决年龄对SCI的影响。 SCI介导的自噬-溶酶体功能失调、AD样神经病理学和 大脑中的神经变性和相关的认知障碍。 由于我们目前的R 01资助范围仅限于短期评估自噬-溶酶体 在急性SCI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， 测试这个假设。我们希望使用这些数据来支持最终的R 01应用程序，以进一步探讨 自噬-溶酶体功能在SCI和AD/痴呆之间的联系。

项目成果

Sexual dimorphism in neurological function after SCI is associated with disrupted neuroinflammation in both injured spinal cord and brain.

• DOI: 10.1016/j.bbi.2021.12.017
• 发表时间: 2022-03
• 期刊: Brain, behavior, and immunity
• 作者: Li Y;Ritzel RM;Lei Z;Cao T;He J;Faden AI;Wu J
• 通讯作者: Wu J

Proton extrusion during oxidative burst in microglia exacerbates pathological acidosis following traumatic brain injury.

• DOI: 10.1002/glia.23926
• 发表时间: 2021-03
• 期刊: Glia
• 影响因子: 6.2
• 作者: Ritzel RM;He J;Li Y;Cao T;Khan N;Shim B;Sabirzhanov B;Aubrecht T;Stoica BA;Faden AI;Wu LJ;Wu J
• 通讯作者: Wu J

Brain injury accelerates the onset of a reversible age-related microglial phenotype associated with inflammatory neurodegeneration.

脑损伤加速了与炎症性神经退行性相关的可逆年龄相关的小胶质细胞表型的发作。

• DOI: 10.1126/sciadv.add1101
• 发表时间: 2023-03-10
• 期刊: Science advances
• 影响因子: 13.6

The voltage-gated proton channel Hv1 plays a detrimental role in contusion spinal cord injury via extracellular acidosis-mediated neuroinflammation.

• DOI: 10.1016/j.bbi.2020.10.005
• 发表时间: 2021-01
• 期刊: Brain, behavior, and immunity
• 作者: Li Y;Ritzel RM;He J;Cao T;Sabirzhanov B;Li H;Liu S;Wu LJ;Wu J
• 通讯作者: Wu J

Functional and transcriptional profiling of microglial activation during the chronic phase of TBI identifies an age-related driver of poor outcome in old mice.

• DOI: 10.1007/s11357-022-00562-y
• 发表时间: 2022-06
• 期刊: GEROSCIENCE
• 影响因子: 5.6
• 作者: Ritzel, Rodney M.;Li, Yun;Lei, Zhuofan;Carter, Jordan;He, Junyun;Choi, Harry M. C.;Khan, Niaz;Li, Hui;Allen, Samantha;Lipinski, Marta M.;Faden, Alan, I;Wu, Junfang
• 通讯作者: Wu, Junfang