The Function and Mechanisms of Autophagy in Spinal Cord Injury

项目摘要 随着治疗和保健的最新进展，脊髓损伤(SCI)患者的预期寿命 在他们的创伤事件发生后的几十年里大幅增加。此外，鉴于 在老年人中，脊髓损伤的风险一直在增加。尽管老龄化是一个关键的风险因素， 认知功能减退与阿尔茨海默病及相关痴呆的发病(AD/ADRD)，近期大规模研究 基于人群的纵向研究表明，脊髓损伤患者患痴呆症的风险很高。 伴随着认知能力的大幅下降。这代表着一个未得到满足的医疗保健挑战。然而，目前还缺乏 大脑中与AD/ADRD的自然脑老化和脑老化轨迹有关的信息 SCI。这种信息是设计有针对性的早期干预措施所必需的，目的是降低感染风险。 脊髓损伤后认知功能下降。自噬-溶酶体途径对于细胞内的脂类、蛋白质和 细胞器降解与质量控制。自噬功能受损与积聚的 病理性蛋白聚集体，如磷酸-tau缠结和淀粉样蛋白β斑块以及随后的神经元 神经退行性疾病中的细胞损伤和死亡。最近的数据表明，与年龄相关的 脊髓损伤加重了脑组织的自噬和溶酶体功能。随之而来的是 脑部炎症和神经变性，表明自噬的扰动可能提供了 SCI和AD/ADRD之间的机械联系。此外，老年人大脑中脂类平衡的破坏可能 会导致自噬缺陷。我们假设脊髓损伤加速了自噬-溶酶体的抑制 通过破坏溶酶体脂稳态在衰老的大脑中发挥作用，最终加重慢性脑损伤。 长期的病理和功能结果和增加的创伤后痴呆风险。 我们将使用具有自噬、低畸形或高激活的年轻成年和老年动物来描绘 自噬-溶酶体途径在脊髓损伤中作为脑病理关键调节因子的作用。HILIC-基于MS/MS的 目标1将使用脂质组学、流式细胞术、互补显微镜和生化方法 确定脂质堆积是否会导致老化大脑中溶酶体功能障碍和自噬抑制 在SCI之后。目标2将确定抑制脊髓损伤后老化大脑中的精确自噬是否会导致 加剧炎症和神经变性，增加患痴呆症的风险。将becn1突变小鼠与 自噬高活性或自然产生的自噬诱导剂海藻糖在老龄小鼠或衰老小鼠中的作用 脊髓损伤后，AIM 3将评估自噬增加对蛋白稳定、神经炎症、 脊髓损伤后与AD/ADRD相关的神经退行性改变和认知结局。 从这些极具意义和创新性的研究中获得的信息将具有重要的 通过确定自噬-溶酶体在脊髓损伤和AD/痴呆之间的联系中的积极作用 通过开发新的潜在治疗干预措施。

Project Summary With recent advances in treatment and healthcare, life expectancy for persons following spinal cord injury (SCI) has increased substantially for several decades after their traumatic event. Moreover, given increased falls in the elderly, the risk of SCI has been increasing in that population. Although aging is a key risk factor for cognitive decline and incident Alzheimer’s Disease and Related Dementia (AD/ADRD), recent large-scale longitudinal population-based studies indicate that patients with SCI are at a high risk of dementia associated with substantial cognitive decline. This represents an unmet health-care challenge. However, there is a lack of information in the brain pertaining to the natural brain aging and brain aging trajectories of AD/ADRD following SCI. Such information is needed for the design of targeted, early interventions aimed at reducing the risk of cognitive decline after SCI. The autophagy-lysosomal pathway is essential for intracellular lipid, 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 β plaques and consequent neuronal cell damage and death in neurodegenerative diseases. Recent data indicate that age related decline in autophagy and lysosomal function in the brain was exacerbated by SCI. This was accompanied by increased brain inflammation and neurodegeneration, suggesting that perturbation of autophagy may provide a mechanistic link between SCI and AD/ADRD. Moreover, disruption of lipid homeostasis in the aged brain may contribute to autophagy defects. We hypothesize that SCI accelerates inhibition of autophagy-lysosomal function in the ageing brain through perturbation of lysosomal lipid homeostasis, ultimately aggravating long- term pathological and functional outcomes and increasing posttraumatic dementia risk. We will use young adult and aged animals with autophagy hypomorph or heperactivation to delineate the roles of autophagy-lysosomal pathway as a key regulator of brain pathology in SCI. HILIC-MS/MS based lipidomics, flow cytometry, complementary microscopy and biochemical approaches will be used in AIM 1 to determine if lipid accumulation causes lysosomal dysfunction and inhibition of autophagy in the ageing brain after SCI. AIM 2 will determine if inhibition of precision autophagy in the ageing brain after SCI leads to exacerbated inflammation and neurodegeneration increasing dementia risk. Using becn1 mutant mice with autophagy heperactivation or a naturally occurring autophagy inducer trehalose in aged mice or mice aging after SCI, AIM 3 will evaluate long-term effects of increased autophagy on proteostasis, neuroinflammation, neurodegeneration and cognitive outcomes relevant to AD/ADRD after SCI. The information gained from these highly significant and innovative studies will have an important positive impact through identifying autophagy-lysosomal function in the link between SCI and AD/dementia and through the development of novel potential therapeutic interventions.