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

项目摘要 流行病学数据将创伤性脑损伤（TBI）史与发生以下疾病的可能性增加联系起来： 阿尔茨海默病（AD）和其他AD相关痴呆（ADRD）在以后的生活中。虽然最近的荟萃分析 据估计，TBI导致痴呆的总体风险为5- 15%，但人们对TBI的病史如何理解仍然知之甚少。 脑外伤可能导致数年甚至数十年后的神经退化。 一种可能性是，TBI可能会加速正常大脑老化过程中发生的有害细胞变化。 一个潜在的候选者是降解错误折叠蛋白质所必需的自噬-溶酶体途径， 受损的细胞器自噬功能在大脑老化过程中下降，在神经退行性疾病中更严重。 疾病因此，与正常对照组相比， 脑老化，可能有助于在AD和其他年龄相关性痴呆中观察到的神经变性。我们最近 表明自噬在TBI后也被抑制。这是由TBI诱导的溶酶体缺陷引起的， 与溶酶体脂质组成的深刻变化有关。溶酶体功能障碍与 也观察到脂褐质和其它脂质副产物在内-溶酶体隔室中的积累， 老年小鼠，并且通过药物或疾病诱导的脱髓鞘发作而加剧。由于TBI导致 髓鞘损伤以及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后的溶酶体抑制，并随着时间的推移导致加速的自噬-溶酶体 与正常老化期间观察到的相比，AD/ADRD的功能障碍，从而导致AD/ADRD。 我们假设TBI后脂质稳态的扰动加速了溶酶体脂质的积累， 与正常衰老相比，导致溶酶体功能障碍和自噬缺陷，从而诱发 神经变性和AD/ADRD。为了验证这一假设，我们将使用基于HILIC-MS/MS的脂质组学 脑溶酶体分析、基于MS的脂质成像和互补IF/IHC和生化方法 比较正常人脑中溶酶体脂质组成和自噬-溶酶体功能的变化， 衰老小鼠和TBI后衰老小鼠。为了测试自噬和脂质代谢紊乱的因果关系， 在AD/ADRD相关病理和认知表型的发展中，我们将使用自噬亚型 Becn 1 +/-小鼠和Scarb 1 +/-小鼠高胆固醇血症。我们还将使用一个飞行TBI模型，以确定额外的 自噬和将TBI与AD/ADRD联系起来的脂质代谢基因。我们希望我们的数据能证明， TBI引起的溶酶体脂质代谢和自噬的扰动是随后的细胞凋亡的重要因素。 AD/ADRD的发展。

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.