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: 10388269
• 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/10388269
• 关键词: 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; Predisposing Factor; 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; base; cell type; dementia risk; epidemiologic data; fly; functional outcomes; 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.

项目总结 流行病学数据将创伤性脑损伤(TBI)病史与脑损伤发生的可能性增加联系起来 阿尔茨海默病(AD)和其他与AD相关的痴呆(ADRD)。虽然最近的荟萃分析 估计可归因于脑外伤的痴呆症的总体风险为5%-15%，但人们仍然很少了解 脑损伤可能会在几年甚至几十年后导致神经退化。 一种可能性是，脑外伤可能会加速正常大脑老化过程中发生的有害细胞变化。 一个潜在的候选途径是自噬-溶酶体途径，对于降解错误折叠的蛋白质和 细胞器受损。自噬功能在脑老化过程中下降，在神经退行性变时更严重 疾病。因此，与正常相比，自噬-溶酶体功能的加速抑制 大脑老化，可能会导致阿尔茨海默病和其他与年龄相关的痴呆患者的神经退化。我们最近 证明了脑外伤后自噬也受到抑制。这是由脑外伤引起的溶酶体缺陷引起的 与溶酶体脂组成的深刻变化有关。溶酶体功能障碍与 脂褐素和其他脂类副产物在内溶酶体内的积聚也被观察到。 衰老的小鼠，药物或疾病引起的脱髓鞘发作会加剧。因为TBI导致了 髓鞘损伤以及更普遍的脑脂代谢紊乱，脂质介导的损伤 也可导致脑外伤后溶酶体抑制，并随着时间的推移导致加速的自噬-溶酶体 与正常衰老时观察到的功能障碍相比，因此导致AD/ADRD。 我们假设，脑创伤后脂质稳态的紊乱加速了溶酶体脂的积聚，即 与正常衰老相比，导致溶酶体功能障碍和自噬缺陷，从而容易 神经退行性变与AD/ADRD为了验证这一假设，我们将使用基于HILIC-MS/MS的脂质体 脑溶酶体分析、基于MS的脂质成像和补充IF/IHC和生化方法 比较正常人脑内溶酶体脂组成和自噬-溶酶体功能的变化 老龄小鼠和脑损伤后衰老小鼠。检测扰动自噬和脂代谢的致病作用 对于AD/ADRD相关的病理和认知表型的发展，我们将采用自噬低晶型 Becn1+/-小鼠和Scar1+/-小鼠高胆固醇血症。我们还将使用Fly TBI模型来确定其他 自噬和脂代谢基因将脑损伤与AD/ADRD联系起来。我们希望我们的数据能证明 脑损伤对溶酶体脂代谢和自噬的干扰是随后 AD/ADRD的发展。