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: 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
• 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' 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; 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

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）的特点是Aβ肽的积累形成淀粉样斑块和超