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Characterizing a potential role for TREM2 in modulating tau pathogenesis in response to Abeta

表征 TREM2 在响应 Abeta 调节 tau 发病机制中的潜在作用

基本信息

批准号：
10360474
负责人：
Timothy Yikai Huang
金额：
$ 24.38万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10360474
关键词：
ATG3 gene Acute Affect Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid beta-Protein Appearance Attenuated Autophagocytosis Behavior Behavioral Binding Biogenesis Biological Assay Biosensor Brain Cell Line Chronic Cognitive deficits Complex Endosomes Etiology Event FRAP1 gene Fluorescence Resonance Energy Transfer Functional disorder Genetic Gliosis Hippocampus (Brain)Human Immunologic Receptors Impaired cognition Impairment In Vitro Interneurons Knock-in Knockout Mice Late Onset Alzheimer Disease Lead Ligands Link Mass Spectrum Analysis Medial Mediating Memory Memory impairment Microglia Modeling Molecular Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Onset of illness Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Phagocytosis Phosphorylation Risk Factors Role Senile Plaques Signal Pathway Signal Transduction Sorting - Cell Movement Sphingomyelinase Synapses System TREM2 gene TYROBP gene Testing Up-Regulation Variant Work abeta accumulation abeta oligomer age related desensitization design differential expression entorhinal cortex exosome hyperphosphorylated tau in vivo inhibitor insight loss of function mouse model neuroinflammation novel novel therapeutics proteotoxicity receptor response sensor synaptic function tau Proteins tau aggregation trafficking transcriptomics uptake

项目摘要

PROJECT SUMMARY Alzheimer's disease (AD) is defined by the appearance of two defining pathologies, namely Aβ-amyloid plaques and neurofibrillary tangles enriched with hyperphosphorylated Tau. Accumulation of Aβ precedes the appearance of pathological Tau, and although correlative evidence indicates that Aβ proteotoxicity and Tau pathology, molecular mechanisms defining how Aβ can directly drive Tau pathogenesis are yet elusive. Recent correlative evidence indicates a role for dysfunction of the microglial immune receptor, Trem2 in enhancing Tau pathogenesis in regions enriched with Aβ plaques in AD mouse models. Interestingly, our previous results indicate that TREM2 is a potential Aβ receptor that directly binds and transduces proteotoxic Aβ signals to drive microglial activation. Given that Trem2 (and the R47H TREM2 variant in humans) is a potent risk factor for AD onset, it seems likely that TREM2 can be a potential link between Aβ and Tau pathology, and potentially modulates Tau pathogenesis with Aβ exposure. Here, we present preliminary results suggesting that Trem2 deletion (KO) in microglia can enhance Tau dispersion from the medial entorhinal cortex (MEC) to the hippocampus, which manifests in behavioral memory impairment and synaptic dysfunction. Transcriptomic analysis of Trem2 KO microglia indicates differential expression of exosomal components, and upregulation of machinery such as Atg12 which drive endosome trafficking and exosomal biogenesis. Our preliminary results in vitro also indicate that microglial Trem2 deletion can enhance transneuronal Tau transduction, which implicates a model where Trem2 deletion may enhance intraneuronal Tau dispersion during AD onset. Our previous results indicate that Aβ oligomers can induce Syk activation, whereas prolonged Aβ exposure can result in progressive renormalization of Syk activity, suggesting that chronic Aβ exposure can “desensitize” microglial TREM2 signaling. Given that the TREM2 R47H likely confers loss-of-function, we will determine whether enhancement of exosome pathways, namely upregulation of Atg12, and/or suppression of the mTOR pathway mediate enhanced Tau pathogenesis with Trem2 deletion, or TREM2 R47H knock-in (KI) in microglia. We will also establish whether long-term Aβ treatment can affect Tau uptake, enhance sorting into exosomes, and extrusion in microglia, and compare differences in exosomal Tau trafficking in WT, Trem2 KO and R47H KI microglia. Using a Tau FRET biosensor cell line system (Tau RD), we will also assay potency of extruded exosomal Tau with long-term Aβ treatment in WT, Trem2 KO and R47H KI backgrounds, and determine whether alterations in Atg12 or mTOR pathways can affect Tau seeding potency. Together, completion of these Aims will provide insight into TREM2 as an intermediary Aβ sensor which initially suppresses Tau dispersion with acute Aβ exposure. Chronic Aβ exposure, however, desensitizes the TREM2 signaling pathway, thereby potentially aggravating Tau exosomal trafficking pathways, and enhancing Tau seeding potency. These findings may lead to novel therapies to uncouple Aβ and Tau pathogenesis in AD.

项目总结阿尔茨海默病(AD)的定义是出现两种决定性的病理，即β-淀粉样斑块和富含过度磷酸化的牛磺酸的神经原纤维缠结。β的积累先于病理性牛磺酸的出现，尽管相关证据表明Aβ蛋白毒性与牛磺酸病理上，Aβ如何直接驱动TAU发病的分子机制尚不清楚。近期相关证据表明小胶质细胞免疫受体TREM2功能障碍在增强Tau中的作用 AD小鼠模型中Aβ斑块富集区的发病机制。有趣的是，我们之前的结果提示TREM2是一种潜在的Aβ受体，可直接结合和转导蛋白毒性Aβ信号驱动小胶质细胞激活。鉴于TREM2(和人类中的R47H TREM2变体)是AD的潜在风险因素发病时，TREM2似乎可能是β和TAU病理之间的潜在联系，并可能通过Aβ暴露调节Tau的发病机制。在这里，我们提出的初步结果表明，TREM2 小胶质细胞中的缺失(KO)可以增加Tau从内侧内嗅皮质(MEC)到海马区，表现为行为记忆障碍和突触功能障碍。转录体对TREM2 KO小胶质细胞的分析表明，外体成分的表达存在差异，并且上调了驱动内体运输和外体生物发生的机制，如ATG12。我们的初步结果是体外实验还表明，小胶质细胞TREM2缺失可以增强跨神经元的Tau转导，这意味着在AD发病过程中，TREM2缺失可能会增加Tau在神经元内的离散。我们以前的结果表明，Aβ寡聚体可以诱导Syk激活，而长时间的Aβ暴露可以导致Syk活性的渐进性重整化，这表明慢性Aβ暴露可以“脱敏” 小胶质细胞TREM2信号转导。鉴于TREM2 R47H可能会导致功能丧失，我们将确定外体途径的增强，即Atg12的上调，和/或mTOR的抑制 TREM2缺失或TREM2 R47H敲入(Ki)在小胶质细胞中介导增强的Tau发病机制。我们还将确定长期的Aβ治疗是否可以影响Tau的摄取，增强对外体的分选，和在小胶质细胞中的挤出，并比较外体Tau在WT、TREM2 KO和R47H KI中转运的差异小胶质细胞。使用Tau FRET生物传感器细胞系系统(Tau RD)，我们还将测试挤压的在WT、TREM2KO和R47HKI背景下长期Aβ治疗的外体Tau，并确定是否 ATG12或mTOR途径的改变会影响Tau的种子活力。总之，这些目标的实现将洞察TREM2作为中介的β传感器最初通过急性抑制Tau扩散一次β曝光。然而，慢性暴露Aβ会使TREM2信号通路变得不敏感，从而潜在地加剧Tau胞外体运输途径，增强Tau种子活力。这些发现可能会导致为解开Aβ和Tau在AD发病机制中的作用提供新的治疗方法。