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:
  • 金额:
    --
  • 依托单位:
  • 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

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。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Sphingolipids in Alzheimer's disease, how can we target them?
  • DOI:
    10.1016/j.addr.2019.12.003
  • 发表时间:
    2020-01-01
  • 期刊:
  • 影响因子:
    16.1
  • 作者:
    Crivelli,Simone M.;Giovagnoni,Caterina;Martinez-Martinez,Pilar
  • 通讯作者:
    Martinez-Martinez,Pilar
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Erhard Bieberich其他文献

Erhard Bieberich的其他文献

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{{ truncateString('Erhard Bieberich', 18)}}的其他基金

Novel experimental models to study the effect of extracellular vesicles on neurons
研究细胞外囊泡对神经元影响的新实验模型
  • 批准号:
    10508346
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
Regulation of Microglial Activation State by a Lipid Transporter
脂质转运蛋白对小胶质细胞激活状态的调节
  • 批准号:
    9887304
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Regulation of Microglial Activation State by a Lipid Transporter
脂质转运蛋白对小胶质细胞激活状态的调节
  • 批准号:
    10112795
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Regulation of Microglial Activation State by a Lipid Transporter
脂质转运蛋白对小胶质细胞激活状态的调节
  • 批准号:
    10536663
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
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
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
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:
    9780683
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
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:
    10412902
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Regulation of cilia by ceramide
神经酰胺对纤毛的调节
  • 批准号:
    9543721
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
Regulation of cilia by ceramide
神经酰胺对纤毛的调节
  • 批准号:
    9175692
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
Ceramide-induced cell death in neurodegeneration
神经退行性变中神经酰胺诱导的细胞死亡
  • 批准号:
    8531806
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:

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衰老和路易体痴呆中不稳定的主动和反应神经力学
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  • 批准号:
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