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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos 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

项目摘要

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.

项目概要流行病学数据将创伤性脑损伤 (TBI) 病史与罹患以下疾病的可能性增加联系起来最近的荟萃分析显示，老年痴呆症（AD）和其他与 AD 相关的痴呆症（ADRD）。据估计 TBI 导致痴呆的总体风险为 5-15%，但人们对 TBI 的病史仍知之甚少。脑外伤可能会导致数年甚至数十年后的神经退行性变。一种可能性是，TBI 可能会加速正常大脑衰老过程中发生的细胞变化。一个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细胞器受损，自噬功能在大脑衰老过程中下降，在神经退行性疾病中更为严重。因此，与正常情况下观察到的相比，自噬溶酶体功能的抑制加速。我们最近观察到，大脑衰老可能会导致 AD 和其他与年龄相关的痴呆症中的神经退行性变。 TBI 后自噬也会受到抑制，这是由 TBI 诱导的溶酶体缺陷引起的。与溶酶体脂质成分的深刻变化有关。还观察到脂褐素和其他脂质副产物在内溶酶体区室中的积累老年小鼠的这种情况会因药物或疾病引起的脱髓鞘事件而加剧，因为 TBI 会导致这种情况。髓磷脂损伤以及大脑中脂质代谢的更普遍的扰动，脂质介导的损伤也可能导致 TBI 后溶酶体抑制，并随着时间的推移导致加速自噬-溶酶体与正常衰老过程中观察到的功能障碍相比，从而导致 AD/ADRD。我们发现，TBI 后脂质稳态的扰动会加速溶酶体脂质积累，如下所示：与正常衰老相比，导致溶酶体功能障碍和自噬缺陷，从而容易为了检验这一假设，我们将使用基于 HILIC-MS/MS 的脂质组学。脑溶酶体分析、基于 MS 的脂质成像以及互补的 IF/IHC 和生化方法比较正常人大脑中溶酶体脂质成分和自噬溶酶体功能的变化衰老小鼠和 TBI 后衰老的小鼠测试自噬和脂质代谢紊乱的因果效应。关于 AD/ADRD 相关病理和认知表型的发展，我们将使用自噬亚形态患有高胆固醇血症的 Becn1+/- 小鼠和 Scarb1+/- 小鼠我们还将使用果蝇 TBI 模型来识别其他疾病。自噬和脂质代谢基因将 TBI 与 AD/ADRD 联系起来。 TBI 对溶酶体脂质代谢和自噬的干扰是随后发生的重要因素 AD/ADRD 的发展。