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.

阿尔茨海默病(AD)的特征是Aβ多肽积聚，形成淀粉样斑块和高淀粉样蛋白。 Tau蛋白的磷酸化形成神经原纤维缠结，这是一个双重的蛋白质聚集过程，导致 进行性神经变性和认知功能衰退。流行病学研究表明，罹患癌症的风险 在经历过头部创伤或创伤性脑损伤(TBI)的人中，AD是前者的4倍 流行于从现役作战归来的退伍军人。风险增加的原因尚不清楚，也没有策略 以防止AD病理的存在。取得进展的一个关键障碍是缺乏对淀粉样蛋白和 Tau具有神经毒性，以及TBI如何诱导或加速这一过程。我们的目标是了解 预防淀粉样蛋白和tau蛋白的神经毒性，延缓AD的发病和减轻神经退行性变， 尤其是在退伍军人中被脑外伤诱发或加速时。我们的中心假设是脑外伤引起的 剪切力动摇并反复弯曲星形胶质细胞内的纤毛，导致钙内流，重新编程 神经酰胺代谢和富含神经酰胺的外切体“星形胶质”的持续分泌 (即日生效)。β42和tau与神经酰胺结合，并将星形体化成神经毒性的β-内体， 甚至在TBI后数年(延迟效应)。Betasome还含有前列腺细胞凋亡反应4(PAR-4)，a 蛋白质使神经元对神经酰胺诱导的细胞凋亡敏感。Betasome被运输到线粒体，在那里 它们增强Aβ42和tau介导的线粒体功能障碍和神经毒性。与我们的 假设，在AD患者和5xFAD小鼠的血清中可以检测到β-内酯酶并诱导线粒体 N2a细胞和原代培养神经元的损伤、caspase激活和tau聚集。我们的假设 预测与Aβ42和tau相关的星形体分泌和神经毒性可以通过阻断来防止 脑损伤诱导的钙内流和神经酰胺的产生。我们的预期结果包括1)确定 神经酰胺上调的酶和剪切力激活的特定钙通道；2) 在星形体中定义神经酰胺组合物，该组合物诱导与Aβ42、tau聚集和 MITO/神经毒性；3)确定神经酰胺调节药物和钙通道阻滞剂 星形胶质分泌、β-内切酶形成、线粒体功能障碍、tau聚集和神经毒性； 4)定量检测血清中反映脑损伤后AD严重程度的星形胶质细胞和β-内酰胺酶。 治疗成功。该项目对保护退伍军人和公共卫生的影响将 包括开发新的治疗策略所需的知识，这些策略可能会延迟和/或预防 阿尔茨海默病的进行性神经退行性变的开始，特别是在退伍军人中由轻微的脑损伤引起的。