Dysregulation of autophagy-lysosomal function links TBI to late-onset neurodegeneration

自噬-溶酶体功能失调将 TBI 与迟发性神经变性联系起来

• 批准号: 10611981
• 负责人: MARTA M LIPINSKI
• 金额: $ 60.21万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10611981
• 关键词: Acceleration; Affect; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Anti-Inflammatory Agents; Apolipoprotein E; Autophagocytosis; Biochemical; Brain; Cholesterol; Cholesterol Homeostasis; Cognitive; Coronary heart disease; Data; Defect; Dementia; Demyelinations; Development; Disease; Feedback; Functional disorder; Genes; Genetic; Genetic Polymorphism; Genetic Screening; High Density Lipoprotein Cholesterol; Homeostasis; Homologous Gene; Image; Inflammation; Inflammatory Response; Injury; Late Onset Alzheimer Disease; Lead; Life; Link; Lipids; Lipofuscin; Long-Term Effects; Lysosomes; Mediating; Meta-Analysis; Modeling; Mus; Mutant Strains Mice; Mutation; Myelin; Nerve Degeneration; Neurodegenerative Disorders; Organelles; Outcome; Pathologic; Pathology; Pathway interactions; Pharmaceutical Preparations; Phenotype; Predisposition; Recording of previous events; SR-BI receptor; Spatial Distribution; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Speed; Testing; Time; Traumatic Brain Injury; age related; aged; aging brain; apolipoprotein E-4; cell type; dementia risk; epidemiologic data; fly; functional outcomes; genetic risk factor; hypercholesterolemia; in vitro Model; inhibition of autophagy; lipid metabolism; lipidomics; misfolded protein; neuroinflammation; normal aging; protein aggregation; proteostasis; spatiotemporal

PROJECT SUMMARY Epidemiological data link history of traumatic brain injury (TBI) to increased likelihood of development of Alzheimer’s Disease (AD) and other AD-related dementias (ADRD) later in life. While recent meta-analyses estimate the overall risk of dementia attributable to TBI at 5-15%, it remains poorly understood how history of brain trauma may contribute to neurodegeneration years or even decades later. One possibility is that TBI may accelerate detrimental cellular changes occurring during normal brain ageing. A potential candidate is the autophagy-lysosomal pathway essential for degrading misfolded proteins and damaged organelles. Autophagy function declines during brain aging and more severely in neurodegenerative diseases. Thus, accelerated inhibition of autophagy-lysosomal function as compared to that observed in normal brain aging, could contribute to neurodegeneration observed in AD and other age-related dementias. We recently demonstrated that autophagy is also inhibited after TBI. This is caused by TBI-induced lysosomal defects and is associated with profound changes in lysosomal lipid composition. Lysosomal dysfunction associated with accumulation of lipofuscin and other lipid byproducts in the endo-lysosomal compartments is also observed in aged mice and is exacerbated by either drug or disease induced demyelinating episodes. Since TBI leads to myelin damage as well as more general perturbation of lipid metabolism in the brain, lipid-mediated damage could also lead to lysosomal inhibition after TBI and over time cause accelerated autophagy-lysosomal dysfunction as compared to that observed during normal aging, thus contributing to AD/ADRD. We hypothesize that perturbation of lipid homeostasis after TBI accelerates lysosomal lipid accumulation as compared to normal aging, leading to lysosomal dysfunction and autophagy defects, thus predisposing to neurodegeneration and AD/ADRD. In order to test this hypothesis, we will use HILIC-MS/MS based lipidomic analysis of brain lysosomes, MS-based lipid imaging and complementary IF/IHC and biochemical approaches to compare changes in lysosomal lipid composition and autophagy-lysosomal function in the brains of normal aging mice and mice aging after TBI. To test the causative effect of perturbed autophagy and lipid metabolism on development of AD/ADRD relevant pathological and cognitive phenotypes we will use autophagy hypomorph Becn1+/- mice and Scarb1+/- mice with hypercholesterolemia. We will also use a fly TBI model to identify additional autophagy and lipid metabolism genes linking TBI to AD/ADRD. We expect that our data will demonstrate that perturbation of lysosomal lipid metabolism and autophagy by TBI is an important contributor to subsequent development of AD/ADRD.

项目摘要 流行病学数据连接创伤性脑损伤（TBI）的历史与增加的可能性 后来，阿尔茨海默氏病（AD）和其他与广告有关的痴呆症（ADRD）。而最近的荟萃分析 估计痴呆症的总体风险归因于TBI，为5-15％，它仍然不太了解 脑部创伤可能会导致神经退行性的几年甚至几十年后。 一种可能性是TBI可能在正常脑老化期间加速有害细胞的变化。 潜在的候选者是自噬 - 溶酶体途径，对于降解错误折叠的蛋白质和 损坏的细胞器。自噬功能在大脑衰老期间下降，并且在神经退行性方面更为严重 疾病。与正常相比 大脑衰老，可能有助于在AD和其他与年龄相关的痴呆症中观察到的神经退行性。 证明在TBI之后，自噬也受到抑制。这是由TBI诱导的溶酶体缺陷引起的，IS 与溶酶体脂质组成的深刻变化有关。溶酶体功能障碍与 还观察到内糖体室中脂肪霉素和其他脂质副产物的积累 老年小鼠，并因药物或疾病引起的脱髓鞘发作而加剧。由于TBI导致 髓磷脂损伤以及更普遍的大脑脂质代谢的扰动，脂质介导的损伤 也可能导致TBI后溶酶体抑制，并且随着时间的流逝会导致加速自噬溶酶体 与正常衰老期间观察到的功能障碍相比，功能障碍会导致AD/ADRD。 我们假设TBI后脂质稳态的扰动会加速溶酶体脂质的积累 与正常衰老相比，导致溶酶体功能障碍和自噬缺陷，因此倾向于 神经变性和AD/ADRD。为了检验这一假设，我们将使用基于Hilic-MS/MS的脂肪组学 脑溶酶体的分析，基于MS的脂质成像和完整的iHC和生化方法 比较正常大脑中溶酶体脂质组成和自噬溶质体功能的变化 TBI后老化的小鼠和小鼠衰老。测试扰动自噬和脂质代谢的致病作用 关于AD/ADRD相关的病理和认知表型的开发 BECN1 +/-小鼠和Scarb1 +/-鼠标高胆固醇血症。我们还将使用Fly TBI模型来识别其他 自噬和脂质代谢基因将TBI连接到AD/ADRD。我们希望我们的数据证明 TBI的溶酶体脂质代谢和自噬的扰动是随后的重要因素 广告/adrd的开发。