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

基本信息

批准号：
10515674
负责人：
Erhard Bieberich
金额：
--
依托单位：
VA MEDICAL CENTER - LEXINGTON, KY
依托单位国家：
美国
项目类别：
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/10515674
关键词：
Acceleration Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Amyloid Amyloid beta-42 Amyloid beta-Protein Apoptosis Astrocytes Axon Binding Brain Calcium Calcium Channel Calcium Channel Blockers Caspase Cell secretion Cells Ceramides Cilia Closed head injuries Craniocerebral Trauma Development Drug Modulation Enzymes Generations Goals Impaired cognition Impairment Induction of Apoptosis Interruption Knowledge Mediating Metabolism Mitochondria Monitor Mus Nerve Degeneration Neurofibrillary Tangles Neurons Outcome Pathology Patients Peptides Persons 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 combat cytochrome c diagnostic biomarker epidemiology study exosome experience hyperphosphorylated tau inhibitor lipid metabolism mild traumatic brain injury mitochondrial dysfunction mouse model neuron loss neurotoxic neurotoxicity novel diagnostics novel therapeutic intervention prevent programs progressive neurodegeneration protein aggregation protein folding response success tau Proteins tau aggregation tau-1 uptake

项目摘要

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）的特征是形成淀粉样蛋白斑块和高度 - Tau蛋白形成神经原纤维缠结的磷酸化，这是一种两倍的蛋白聚集过程进行性神经变性和认知能力下降。流行病学研究表明，发展的风险患有头部创伤或脑外伤（TBI）的人的AD高4倍在活跃战斗中返回的退伍军人中普遍存在。这种增加风险的原因尚不清楚，没有策略为了防止AD病理存在。进步的关键障碍是缺乏对淀粉样蛋白和淀粉样蛋白的了解 TAU是神经毒性的，TBI如何诱导或加速此过程。我们的目标是了解并防止淀粉样蛋白和tau神经毒性，并延迟发作并减少AD中的神经变性，特别是当TBI在退伍军人中诱导或加速时。我们的中心假设是TBI诱导剪切力摇动并反复弯曲星形胶质细胞，从而导致钙影响，重新编程神经酰胺的代谢，并持续分泌富含神经酰胺的外泌体（直接效果）。 Aβ42和TAU与神经酰胺相关，并将天体变成神经毒性β，即甚至在TBI之后的几年（效应延迟）。 β还包含前列腺凋亡反应4（PAR-4），A 蛋白质对神经酰胺诱导的细胞凋亡敏感。 β分子被运送到线粒体，那里它们增强了Aβ42和Tau介导的线粒体功能障碍和神经毒性。与我们一致假设，可在AD患者和5XFAD小鼠的血清中检测到β-可检测到线粒体 N2A细胞和原发性培养神经元中的损伤，胱天蛋白酶激活和TAU聚集。我们的假设预测天体分泌，与Aβ42和TAU的关联以及神经毒性可以通过阻塞来阻止 TBI诱导的钙影响和神经酰胺的产生。我们的预期结果包括1）确定神经酰胺和特定钙通道上调的酶被剪切力激活； 2）定义天体中的神经酰胺组成，从而影响与Aβ42，tau聚集和的相互作用 MITO/神经毒性； 3）识别可防止的神经酰胺调节药物和钙通道阻滞剂天体分泌，β形成，线粒体功能障碍以及tau聚集和神经毒性； 4）在血清中量化的星体和β，表明TBI诱导的AD（TBI-AD）和治疗的成功。该项目对退伍军人和公共卫生保护的影响将包括开发新治疗策略所需的知识，这些策略可能会延迟和/或阻止 AD进行性神经退行性的发作，特别是在退伍军人中由轻度TBI诱导时。