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:
- 金额:$ 24.38万
- 依托单位:
- 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:
- 关键词:ATG3 geneAcuteAffectAlzheimer&aposs DiseaseAlzheimer&aposs disease riskAmyloid beta-ProteinAppearanceAttenuatedAutophagocytosisBehaviorBehavioralBindingBiogenesisBiological AssayBiosensorBrainCell LineChronicCognitive deficitsComplexEndosomesEtiologyEventFRAP1 geneFluorescence Resonance Energy TransferFunctional disorderGeneticGliosisHippocampus (Brain)HumanImmunologic ReceptorsImpaired cognitionImpairmentIn VitroInterneuronsKnock-inKnockout MiceLate Onset Alzheimer DiseaseLeadLigandsLinkMass Spectrum AnalysisMedialMediatingMemoryMemory impairmentMicrogliaModelingMolecularNerve DegenerationNeurodegenerative DisordersNeurofibrillary TanglesOnset of illnessPathogenesisPathogenicityPathologicPathologyPathway interactionsPhagocytosisPhosphorylationRisk FactorsRoleSenile PlaquesSignal PathwaySignal TransductionSorting - Cell MovementSphingomyelinaseSynapsesSystemTREM2 geneTYROBP geneTestingUp-RegulationVariantWorkabeta accumulationabeta oligomerage relateddesensitizationdesigndifferential expressionentorhinal cortexexosomehyperphosphorylated tauin vivoinhibitorinsightloss of functionmouse modelneuroinflammationnovelnovel therapeuticsproteotoxicityreceptorresponsesensorsynaptic functiontau Proteinstau aggregationtraffickingtranscriptomicsuptake
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。
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)
Trem2 deletion enhances tau dispersion and pathology through microglia exosomes.
- DOI:10.1186/s13024-022-00562-8
- 发表时间:2022-09-02
- 期刊:
- 影响因子:15.1
- 作者:
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Timothy Yikai Huang其他文献
Timothy Yikai Huang的其他文献
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{{ truncateString('Timothy Yikai Huang', 18)}}的其他基金
Elucidating a microgliaassociated role for SORLA in modulating AD pathogenesis
阐明 SORLA 在调节 AD 发病机制中的小胶质细胞相关作用
- 批准号:
10455261 - 财政年份:2022
- 资助金额:
$ 24.38万 - 项目类别:
"A Novel Role for the UPR Component, ATF6 in AD-associated Neuroprotective Pathways"
“UPR 成分 ATF6 在 AD 相关神经保护途径中的新作用”
- 批准号:
10132964 - 财政年份:2019
- 资助金额:
$ 24.38万 - 项目类别:
"A Novel Role for the UPR Component, ATF6 in AD-associated Neuroprotective Pathways"
“UPR 成分 ATF6 在 AD 相关神经保护途径中的新作用”
- 批准号:
10563219 - 财政年份:2019
- 资助金额:
$ 24.38万 - 项目类别:
"A Novel Role for the UPR Component, ATF6 in AD-associated Neuroprotective Pathways"
“UPR 成分 ATF6 在 AD 相关神经保护途径中的新作用”
- 批准号:
10353397 - 财政年份:2019
- 资助金额:
$ 24.38万 - 项目类别:
Novel roles for the Alzheimer's Disease (AD) risk gene, SORLA in neuroprotection in AD
阿尔茨海默病 (AD) 风险基因 SORLA 在 AD 神经保护中的新作用
- 批准号:
10404609 - 财政年份:2018
- 资助金额:
$ 24.38万 - 项目类别:
Novel roles for the Alzheimer's Disease (AD) risk gene, SORLA in neuroprotection in AD
阿尔茨海默病 (AD) 风险基因 SORLA 在 AD 神经保护中的新作用
- 批准号:
9788245 - 财政年份:2018
- 资助金额:
$ 24.38万 - 项目类别:
Novel roles for the Alzheimer's Disease (AD) risk gene, SORLA in neuroprotection in AD
阿尔茨海默病 (AD) 风险基因 SORLA 在 AD 神经保护中的新作用
- 批准号:
9925791 - 财政年份:2018
- 资助金额:
$ 24.38万 - 项目类别:
Molecular pathobiology of soluble TREM2 in Alzheimer's disease
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- 批准号:
10737172 - 财政年份:2017
- 资助金额:
$ 24.38万 - 项目类别:
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