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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.

项目摘要阿尔茨海默病（AD）的定义是两种定义性病理的出现，即A β-淀粉样蛋白斑块和富含过度磷酸化Tau的神经元缠结。A β的蓄积先于病理性Tau的出现，虽然相关证据表明A β蛋白毒性和Tau 在病理学上，定义A β如何直接驱动Tau发病机制的分子机制仍然难以捉摸。最近相关证据表明小胶质细胞免疫受体Trem2功能障碍在增强Tau蛋白表达中的作用。 AD小鼠模型中富含A β斑块区域的发病机制。有趣的是，我们之前的研究结果表明TREM2是一种潜在的A β受体，其直接结合并转导蛋白毒性A β信号以驱动小胶质细胞激活。鉴于Trem2（以及人类中的R47H TREM2变体）是AD的潜在风险因素，发病时，TREM2似乎可能是A β和Tau病理学之间的潜在联系，通过A β暴露调节Tau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Tau基因缺失（KO）可以增强Tau从内侧内嗅皮层（MEC）到下丘脑的分散。海马，表现为行为记忆障碍和突触功能障碍。转录组 Trem2 KO小胶质细胞的分析表明外泌体组分的差异表达，以及例如驱动内体运输和外泌体生物发生的Atg12机制。我们的初步结果，体外也表明小胶质细胞Trem2缺失可以增强跨神经元Tau转导，这暗示了 Trem2缺失可增强AD发作期间神经元内Tau分散的模型。我们以前的研究结果表明，A β寡聚体可以诱导Syk活化，而长期A β暴露可以诱导Syk活化。导致Syk活性的进行性重新正常化，表明慢性A β暴露可以"脱敏" 小胶质细胞TREM2信号传导。鉴于TREM2 R47 H可能导致功能丧失，我们将确定无论是增强外泌体途径，即上调Atg 12，和/或抑制mTOR 在小胶质细胞中，Trem2缺失或TREM2 R47H敲入（KI）介导增强的Tau发病机制。我们还将确定长期A β治疗是否会影响Tau的摄取，增强外泌体的分选，和挤出，并比较WT、Trem2 KO和R47H KI中外泌体Tau运输的差异小胶质细胞使用Tau FRET生物传感器细胞系系统（Tau RD），我们还将测定挤出的重组蛋白的效力。在WT、Trem2 KO和R47 H KI背景下，用长期A β治疗外泌体Tau，并确定 Atg12或mTOR途径的改变可影响Tau接种效力。总之，完成这些目标将提供了对TREM2作为中间A β传感器的深入了解，该传感器最初抑制Tau分散， A β暴露。然而，慢性A β暴露会使TREM2信号通路脱敏，从而可能加重Tau外泌体运输途径，并增强Tau播种效力。这些发现可能会导致本发明涉及在AD中解偶联A β和Tau发病机制的新疗法。