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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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos 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

项目摘要

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.

项目总结

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
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
影响因子：
0
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