TBI-induced exosome release accelerates Alzheimer's disease pathology

TBI诱导的外泌体释放加速阿尔茨海默病病理学

• 批准号: 10044406
• 负责人: Erhard Bieberich
• 金额: --
• 依托单位: VA MEDICAL CENTER - LEXINGTON, KY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10044406
• 关键词: Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Apoptosis; Astrocytes; Axon; Binding; Brain; Calcium; Calcium Channel; Calcium Channel Blockers; Caspase; Cells; Ceramides; Cilia; Closed head injuries; Craniocerebral Trauma; Development; Enzymes; Generations; Goals; Impaired cognition; Impairment; Interruption; Knowledge; Mediating; Metabolism; Mitochondria; Monitor; Mus; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Outcome; Pathology; Patients; Peptides; Persons; Pharmaceutical Preparations; Prevention; Process; Prostate; Proteins; Public Health; Research; Risk; Senile Plaques; Serum; Severities; Testing; Therapeutic; Traumatic Brain Injury; Up-Regulation; Vesicle; Veterans; Voltage-Dependent Anion Channel; amyloid peptide; axonal degeneration; cell motility; ceramide 3; combat; cytochrome c; diagnostic biomarker; epidemiology study; exosome; experience; inhibitor/antagonist; lipid metabolism; mild traumatic brain injury; mitochondrial dysfunction; mouse model; neuron loss; neurotoxic; neurotoxicity; novel diagnostics; prevent; progressive neurodegeneration; protein aggregation; protein folding; response; success; tau Proteins; tau aggregation; tau-1; treatment strategy; uptake

Alzheimer's disease (AD) is characterized by build-up of Aβ peptides forming amyloid plaques and hyper- phosphorylation of tau protein forming neurofibrillary tangles, a two-fold protein aggregation process leading to progressive neurodegeneration and cognitive decline. Epidemiological studies show that the risk of developing AD is 4-fold higher in persons who have experienced head trauma or traumatic brain injury (TBI), which is prevalent in Veterans returning from active combat. Reasons for this increased risk are unclear and no strategy to prevent AD pathology exists. A critical barrier to progress is the lack of understanding of how amyloid and tau are rendered neurotoxic, and how TBI may induce or accelerate this process. Our goal is to understand and prevent amyloid and tau neurotoxicity and delay the onset and reduce neurodegeneration in AD, particularly when induced or accelerated by TBI in Veterans. Our central hypothesis is that TBI-induced shear force shakes and repeatedly bends cilia in astrocytes, which leads to calcium influx, reprogramming of ceramide metabolism, and sustained secretion of ceramide-enriched exosomes termed “astrosomes” (immediate effect). Aβ42 and tau associate with ceramide and turn astrosomes into neurotoxic betasomes, even years after TBI (delayed effect). Betasomes also contain prostate apoptosis response 4 (PAR-4), a protein sensitizing neurons to ceramide-induced apoptosis. Betasomes are transported to mitochondria, where they enhance Aβ42 and tau-mediated mitochondrial dysfunction and neurotoxicity. Consistent with our hypothesis, betasomes are detectable in serum from AD patients and 5xFAD mice and induce mitochondrial damage, caspase activation, and tau aggregation in N2a cells and primary cultured neurons. Our hypothesis predicts that astrosome secretion, association with Aβ42 and tau, and neurotoxicity are prevented by blocking TBI-induced calcium influx and ceramide generation. Our expected outcomes include 1) determining enzymes in upregulation of ceramide and specific calcium channels that are activated by shear force; 2) defining a ceramide composition in astrosomes that induces interaction with Aβ42, tau aggregation, and mito/neurotoxicity; 3) identifying ceramide-modulating drugs and calcium channel blockers that prevent astrosome secretion, betasome formation, mitochondrial dysfunction, and tau aggregation and neurotoxicity; and 4) quantifying astrosomes and betasomes in serum that indicate severity of TBI-induced AD (TBI-AD) and success of therapeutic treatment. The impact of this project on protection of Veterans and public health will include knowledge needed for the development of new treatment strategies that could delay and/or prevent the onset of progressive neurodegeneration in AD, in particular when induced by mild TBI in Veterans.

阿尔茨海默氏病 (AD) 的特点是 Aβ 肽积聚，形成淀粉样斑块和过度增生。 tau 蛋白磷酸化形成神经原纤维缠结，这是一个双重蛋白质聚集过程，导致 流行病学研究表明，存在进行性神经变性和认知能力下降的风险。 经历过头部外伤或创伤性脑损伤 (TBI) 的人的 AD 发病率高出 4 倍，即 这种风险增加的原因尚不清楚，也没有策略。 预防AD病理存在的一个关键障碍是缺乏对淀粉样蛋白和淀粉样蛋白如何作用的了解。 tau 蛋白具有神经毒性，以及 TBI 如何诱导或加速这一过程。 预防和减少淀粉样蛋白和 tau 蛋白神经毒性，延缓 AD 发病并减少神经变性， 特别是当退伍军人因 TBI 诱发或加速时，我们的中心假设是 TBI 诱发。 剪切力震动并反复弯曲星形胶质细胞中的纤毛，从而导致钙流入，重新编程 神经酰胺代谢，以及富含神经酰胺的外泌体（称为“星体”）的持续分泌 （立即生效）。Aβ42 和 tau 蛋白与神经酰胺结合，将星体转化为神经毒性β体， 即使在 TBI 数年后（延迟效应），Betasome 也含有前列腺细胞凋亡反应 4 (PAR-4)。 使神经元对神经酰胺诱导的细胞凋亡敏感的蛋白质正在转运至线粒体。 它们增强 Aβ42 和 tau 介导的线粒体功能障碍和神经毒性，这与我们的研究一致。 假设，在 AD 患者和 5xFAD 小鼠的血清中可以检测到 betasome，并诱导线粒体 N2a 细胞和原代培养神经元中的损伤、半胱天冬酶激活和 tau 聚集。 预测星体分泌、与 Aβ42 和 tau 的关联以及神经毒性可以通过阻断来预防 TBI 诱导的钙流入和神经酰胺生成包括 1) 确定。 剪切力激活的神经酰胺和特定钙通道上调酶；2) 定义了天体中的神经酰胺成分，可诱导与 Aβ42、tau 聚集和 线粒体/神经毒性；3) 确定可预防的神经酰胺调节药物和钙通道阻滞剂 星体分泌、β体形成、线粒体功能障碍、tau蛋白聚集和神经毒性； 4) 量化血清中的星体和β体，以指示 TBI 诱导的 AD (TBI-AD) 的严重程度； 该项目对退伍军人保护和公共卫生的影响将取得成功。 包括制定新的治疗策略所需的知识，这些策略可以延迟和/或预防 AD 中出现进行性神经变性，特别是退伍军人中由轻度 TBI 引起的情况。