Activation of TREM2 via single-domain antibodies improves synaptic and cognitive function in 5×FAD mice.

IF 7.7 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2026-09-26 DOI:10.1016/j.celrep.2026.118063

Xiaoxiao Yu, Qiaoyun Ren, Yanchun Gao, Sha Xie, Rui Dang, Jinguo Meng, Zhipeng Su, Meng Li, Yuanbo Ao, An Liu, Yanan Wang, Wei Xie

{"title":"Activation of TREM2 via single-domain antibodies improves synaptic and cognitive function in 5×FAD mice.","authors":"Xiaoxiao Yu, Qiaoyun Ren, Yanchun Gao, Sha Xie, Rui Dang, Jinguo Meng, Zhipeng Su, Meng Li, Yuanbo Ao, An Liu, Yanan Wang, Wei Xie","doi":"10.1016/j.celrep.2026.118063","DOIUrl":null,"url":null,"abstract":"<p><p>Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, and dysfunction of triggering receptor expressed on myeloid cells 2 (TREM2) in microglia increases AD risk. TREM2 activation promotes protective microglial functions and mitigates AD pathology. Although TREM2-activating antibodies show therapeutic potential, the mechanisms underlying TREM2-mediated rescue effects remain unclear. Here, we show that two TREM2-activating single-domain antibodies (sdAbs), 10C11 and 10E12, activate microglia and rescue cognitive deficits in early-stage transgenic mice with five familial Alzheimer's disease mutations (5×FAD) following ventral hippocampal injection. 10E12 reduces Aβ plaques and preserves synaptic function, whereas 10C11 protects synapses without affecting plaque burden. Both antibodies reduce C1q levels in AD model mice, suggesting that TREM2 activation exerts multifaceted functions in AD. Together, this study presents two TREM2-targeting sdAbs with AD therapeutic potential and provides insights into the cellular mechanisms underlying TREM2 activation and microglial modulation.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"45 10","pages":"118063"},"PeriodicalIF":7.7000,"publicationDate":"2026-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell reports","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.celrep.2026.118063","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, and dysfunction of triggering receptor expressed on myeloid cells 2 (TREM2) in microglia increases AD risk. TREM2 activation promotes protective microglial functions and mitigates AD pathology. Although TREM2-activating antibodies show therapeutic potential, the mechanisms underlying TREM2-mediated rescue effects remain unclear. Here, we show that two TREM2-activating single-domain antibodies (sdAbs), 10C11 and 10E12, activate microglia and rescue cognitive deficits in early-stage transgenic mice with five familial Alzheimer's disease mutations (5×FAD) following ventral hippocampal injection. 10E12 reduces Aβ plaques and preserves synaptic function, whereas 10C11 protects synapses without affecting plaque burden. Both antibodies reduce C1q levels in AD model mice, suggesting that TREM2 activation exerts multifaceted functions in AD. Together, this study presents two TREM2-targeting sdAbs with AD therapeutic potential and provides insights into the cellular mechanisms underlying TREM2 activation and microglial modulation.

查看原文本刊更多论文

通过单域抗体激活TREM2可改善5×FAD小鼠的突触和认知功能。

阿尔茨海默病（Alzheimer's disease， AD）是最常见的神经退行性疾病，而小胶质细胞中髓样细胞2 （TREM2）触发受体表达功能障碍增加了AD的风险。TREM2激活促进保护性小胶质细胞功能并减轻AD病理。虽然trem2激活抗体显示出治疗潜力，但trem2介导的拯救作用的机制尚不清楚。在这里，我们展示了两种激活trem2的单域抗体（sabs）， 10C11和10E12，激活小胶质细胞，并在患有5个家族性阿尔茨海默病突变的早期转基因小鼠（5×FAD）进行腹侧海马注射后，挽救认知缺陷。10E12减少β斑块并保持突触功能，而10C11保护突触而不影响斑块负担。这两种抗体都降低了AD模型小鼠的C1q水平，表明TREM2激活在AD中具有多方面的功能。总之，本研究提出了两种具有治疗潜力的TREM2靶向单克隆抗体，并为TREM2激活和小胶质细胞调节的细胞机制提供了见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.