Molecular pathobiology of soluble TREM2 in Alzheimer's disease

可溶性 TREM2 在阿尔茨海默病中的分子病理学

• 批准号: 10737172
• 负责人: Timothy Yikai Huang
• 金额: $ 265.58万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737172
• 关键词: Abeta clearance; Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-Protein; Animals; Behavior; Binding; Brain; Cell Line; Cell model; Cerebrospinal Fluid; Exhibits; Family; Gliosis; Histology; Human; Immunologic Receptors; Impaired cognition; In Vitro; Inflammation; Late Onset Alzheimer Disease; Length; Ligands; Link; Manuscripts; Mediating; Membrane; Microglia; Modeling; Molecular; Mus; Mutation; Neurites; Neurodegenerative Disorders; Neurofibrillary Tangles; Onset of illness; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Peptide Hydrolases; Phagocytosis; Phenotype; Process; Risk; Role; Senile Plaques; Site; System; TREM2 gene; TYROBP gene; Up-Regulation; Variant; Work; Xenograft Model; Xenograft procedure; abeta accumulation; abeta deposition; abeta oligomer; abeta toxicity; exosome; gain of function; genetic risk factor; glial activation; in vivo; induced pluripotent stem cell; insight; loss of function; neuroprotection; receptor; response; sensor; tau Proteins; tau aggregation; tau expression; tau-1; trafficking; transcriptome sequencing; uptake

PROJECT SUMMARY Alzheimer’s disease (AD) is the most prominent neurodegenerative disorder worldwide, and is pathologically characterized by Aβ plaques and tau tangles. Growing evidence indicates that microglial receptors such as TREM2 can play a role in both Aβ and tau pathology. TREM2 is proteolytically processed by ADAM proteases to generate soluble TREM2 (sTREM2). Although sTREM2 levels are significantly elevated in cerebrospinal fluid (CSF) along with tau and phospho-tau during early stages of AD onset, nothing was known with respect to sTREM2 function prior to our previous R01 study. Our group and others established that TREM2 is a potential Aβ receptor which mediates microglial activation in response to Aβ oligomers (Zhao et al., 2018). Moreover, our prior mPI team showed that AAV-mediated sTREM2 expression could reduce Aβ accumulation and promote microglial activation (Zhong et al., 2019). Interestingly, the TREM2 cleavage site was recently shown to occur at H157, where an AD-associated H157Y TREM2 variant enhanced TREM2 ADAM-dependent TREM2 cleavage. We therefore integrated the H157Y mutation into the murine Trem2 locus, and characterized effects of H157Y Trem2 in a 5xFAD background. We found that similar to sTREM2 expression, H157Y Trem2 reduced Aβ plaque load and enhanced Aβ clearance, suggesting that enhanced sTREM2 associated with H157Y Trem2 can reduce Aβ. Unexpectedly, we also observed that unlike sTREM2, H157Y Trem2 suppressed microglial activation signatures (manuscript in revision), suggesting that in addition to potential sTREM2-dependent effects associated with enhanced sTREM2 shedding, H157Y Trem2 may also be associated with potential loss-of- function phenotypes linked to elevated TREM2 cleavage and inactivation. A key question remains how H157Y Trem2 can enhance Aβ clearance, and is yet associated with elevated AD risk. Our results indicate that Trem2 deletion can aggravate tau dispersion and pathogenesis through enhancing distribution of seed-competent tau in microglial exosomes (Zhu et al., 2022). Our preliminary results also indicate that sTREM2 enhances internalization of tau oligomers in microglia, and promotes trafficking of internalized tau to pre-exosomal compartments, which suggests that although H157Y Trem2 confers neuroprotective effects with respect to Aβ clearance, H157Y Trem2 could potentially aggravate tau pathology through combined gain-of-function (sTREM2) and loss-of-function (TREM2 cleavage/inactivation) effects. To decipher gain and loss-of-function effects associated with H157Y Trem2 with respect to Aβ and tau, we propose to use a combination of mouse AD (5xFAD, PS19; AAV-tau dispersion models) and human cell models (ESC- derived microglia models) to distinguish between effects of Trem2 KO, H157Y and sTREM2 on Aβ and tau pathology and microglial activation states, as well as distinguish effects of H157Y TREM2 in mouse and human microglia using ESC-derived xenotransplantation models in hMCSF/5xFAD mouse brain. This will allow us to decipher sTREM2-dependent and independent effects associated with H157Y TREM2 in AD pathology.

项目摘要 阿尔茨海默氏病（AD）是全球最突出的神经退行性疾病，在病理上是 以Aβ斑块和tau缠结为特征。越来越多的证据表明，小胶质受体，例如 TREM2可以在Aβ和TAU病理学中发挥作用。 TREM2由亚当蛋白酶蛋白水解处理 为了产生固体TREM2（Streem2）。尽管脑脊液中的Streem2水平显着升高 （CSF）与tau和phospho-tau一起在AD发作的早期阶段，关于 在我们先前的R01研究之前，Streem2功能。我们的小组和其他人确定TREM2是一种潜力 响应Aβ低聚物的小胶质细胞活化的Aβ受体（Zhao等，2018）。而且，我们的 先前的MPI团队表明，AAV介导的streem2表达可以减少Aβ的积累并促进 小胶质激活（Zhong等，2019）。有趣的是，最近显示出在 H157，其中与AD相关的H157Y TREM2变体增强了TREM2 ADAM依赖性Trem2裂解。 因此，我们将H157Y突变整合到鼠TREM2基因座中，并表征了H157Y的作用 trem2在5xfad背景中。我们发现类似于Streem2表达，H157Y TREM2减少了Aβ斑块 负载和增强的Aβ间隙，表明与H157Y TREM 2相关的增强的Strem2可以减少 Aβ。出乎意料的是，我们还观察到，与Strem2不同，H157Y TREM2抑制了小胶质细胞激活 签名（修订中的手稿），表明除了潜在的streem2依赖性效果外 与增强的Streem2脱落相关，H157Y TREM2也可能与潜在的丧失有关 功能表型与升高的Trem2裂解和灭活有关。 一个关键问题是H157Y TREM2如何增强Aβ清除率，并且仍然与升高有关 广告风险。我们的结果表明，trem2删除可以通过 增强小胶质细胞外泌体中种子能力的Tau的分布（Zhu等，2022）。我们的初步结果 还表明Streem2增强了小胶质细胞中Tau低聚物的内在化，并促进了贩运 内部化的t​​au到前诊断室，这表明尽管H157Y trem2既赋予了 关于Aβ清除率的神经保护作用，H157Y TREM2可能会加剧tau病理 通过共同的功能获得（Streem2）和功能丧失（TREM2裂解/灭活）效应。到 根据Aβ和TAU，与H157Y TREM2相关的解密增益和功能丧失效应，我们提出 使用小鼠AD（5xFAD，PS19； AAV-TAU分散模型）和人类细胞模型（ESC- 衍生的小胶质细胞模型）以区分trem2 KO，H157Y和Streem2对Aβ和TAU的影响 病理和小胶质激活状态，以及H157Y TREM2在小鼠和人类中的明显影响 使用ESC衍生的异种移植模型中的小胶质细胞中的HMCSF/5XFAD小鼠大脑。这将使我们能够 与H157Y TREM2相关的DECIPHER StREM2依赖性和独立效应在AD病理学中。

项目成果

Soluble TREM2 ameliorates pathological phenotypes by modulating microglial functions in an Alzheimer's disease model

可溶性 TREM2 通过调节阿尔茨海默病模型中的小胶质细胞功能来改善病理表型。

• DOI: 10.1038/s41467-019-09118-9
• 发表时间: 2019-03-25
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Zhong, Li;Xu, Ying;Chen, Xiao-Fen
• 通讯作者: Chen, Xiao-Fen

Amyloid-beta modulates microglial responses by binding to the triggering receptor expressed on myeloid cells 2 (TREM2).

β 淀粉样蛋白通过与髓样细胞 2 (TREM2) 上表达的触发受体结合来调节小胶质细胞反应。

• DOI: 10.1186/s13024-018-0247-7
• 发表时间: 2018-03-27
• 期刊: Molecular neurodegeneration
• 影响因子: 15.1
• 作者: Zhong L;Wang Z;Wang D;Wang Z;Martens YA;Wu L;Xu Y;Wang K;Li J;Huang R;Can D;Xu H;Bu G;Chen XF
• 通讯作者: Chen XF

Arginine Methyltransferase PRMT8 Provides Cellular Stress Tolerance in Aging Motoneurons.

精氨酸甲基转移酶 PRMT8 为衰老运动神经元提供细胞应激耐受性。

• DOI: 10.1523/jneurosci.3389-17.2018
• 发表时间: 2018
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Simandi,Zoltan;Pajer,Krisztian;Karolyi,Katalin;Sieler,Tatiana;Jiang,Lu-Lin;Kolostyak,Zsuzsanna;Sari,Zsanett;Fekecs,Zoltan;Pap,Attila;Patsalos,Andreas;Contreras,GerardoAlvarado;Reho,Balint;Papp,Zoltan;Guo,Xiufang;Horvath,Attil
• 通讯作者: Horvath,Attil

Association study between multiple system atrophy and TREM2 p.R47H.

多系统萎缩与TREM2 p.R47H之间的关联研究。

• DOI: 10.1212/nxg.0000000000000257
• 发表时间: 2018
• 期刊: Neurology. Genetics
• 作者: Ogaki,Kotaro;Heckman,MichaelG;Koga,Shunsuke;Martens,YukaA;Labbé,Catherine;Lorenzo-Betancor,Oswaldo;Walton,RonaldL;Soto,AlexandraI;Vargas,EmilyR;Fujioka,Shinsuke;Uitti,RyanJ;vanGerpen,JayA;Cheshire,WilliamP;Younkin,Steve
• 通讯作者: Younkin,Steve

Intracellular trafficking of TREM2 is regulated by presenilin 1.

• DOI: 10.1038/emm.2017.200
• 发表时间: 2017-12-01
• 期刊: Experimental & molecular medicine
• 影响因子: 12.8
• 作者: Zhao Y;Li X;Huang T;Jiang LL;Tan Z;Zhang M;Cheng IH;Wang X;Bu G;Zhang YW;Wang Q;Xu H
• 通讯作者: Xu H