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携带TREM2突变的血液单核细胞在阿尔茨海默病发病机制中的作用及其对APP/PS1小鼠的治疗潜力。

Roles of blood monocytes carrying TREM2 mutation in pathogenesis of Alzheimer's disease and its therapeutic potential in APP/PS1 mice.

作者信息

Yu Zhong-Yuan, Liu Jie, Liu Zhi-Hao, Liu Xiao-Yu, Tuo Jin-Mei, Li Jiang-Hui, Tu Yun-Feng, Tan Qi, Ma Yuan-Yuan, Bai Yu-Di, Xin Jia-Yan, Huang Shan, Zeng Gui-Hua, Shi An-Yu, Wang Jun, Liu Yu-Hui, Bu Xian-Le, Ye Li-Lin, Wan Ying, Liu Tong-Fei, Chen Xiao-Wei, Qiu Zi-Long, Gao Chang-Yue, Wang Yan-Jiang

机构信息

Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China.

Institute of Brain and Intelligence, Chongqing, China.

出版信息

Alzheimers Dement. 2025 Feb;21(2):e14402. doi: 10.1002/alz.14402. Epub 2024 Dec 30.

DOI:10.1002/alz.14402
PMID:39740209
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11848385/
Abstract

INTRODUCTION

The triggering receptor expressed on myeloid cells 2 (TREM2) arginine-47-histidine (R47H) mutation is a significant risk for Alzheimer's disease (AD) with unclear mechanisms. Previous studies focused on microglial amyloid-β (Aβ) phagocytosis with less attention on the impact of TREM2 mutation on blood monocytes.

METHODS

Bone marrow transplantation (BMT) models were used to assess the contribution of blood monocytes carrying TREM2 mutation to AD.

RESULTS

Aβ phagocytosis was compromised in mouse monocytes carrying the TREM2 mutation. Transplantation of bone marrow cells (BMCs) carrying TREM2 mutation increased cerebral Aβ burden and aggravated AD-type pathologies. Moreover, the replacement of TREM2-BMCs restored monocytic Aβ phagocytosis, lowered Aβ levels in the blood and brain, and improved cognitive function.

DISCUSSION

Our study reveals that blood monocytes carrying the TREM2 mutation substantially contribute to the pathogenesis of AD, and correcting the TREM2 mutation in BMCs would be a potential therapeutic approach for those carrying this mutation.

HIGHLIGHTS

TREM2 mutation compromises the Aβ phagocytosis of blood monocytes. Blood monocytes carrying TREM2 mutation contribute substantially to AD pathogenesis. Correction of the TREM2 mutation in bone marrow cells ameliorates AD pathologies and cognitive impairments.

摘要

引言

髓系细胞触发受体2（TREM2）精氨酸47-组氨酸（R47H）突变是阿尔茨海默病（AD）的一个重大风险因素，但其机制尚不清楚。以往的研究主要集中在小胶质细胞对淀粉样β蛋白（Aβ）的吞噬作用上，而较少关注TREM2突变对血液单核细胞的影响。

方法

采用骨髓移植（BMT）模型来评估携带TREM2突变的血液单核细胞对AD的影响。

结果

携带TREM2突变的小鼠单核细胞中Aβ吞噬作用受损。移植携带TREM2突变的骨髓细胞（BMC）会增加脑内Aβ负担并加重AD型病理变化。此外，替换TREM2 - BMC可恢复单核细胞的Aβ吞噬作用，降低血液和脑内的Aβ水平，并改善认知功能。

讨论

我们的研究表明，携带TREM2突变的血液单核细胞在很大程度上促成了AD的发病机制，而纠正BMC中的TREM2突变可能是针对携带该突变者的一种潜在治疗方法。

要点

TREM2突变损害血液单核细胞的Aβ吞噬作用。携带TREM2突变的血液单核细胞在很大程度上促成AD发病机制。纠正骨髓细胞中的TREM2突变可改善AD病理变化和认知障碍。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/944a/11848385/7438df59ada4/ALZ-21-e14402-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/944a/11848385/f1bd1c1440ef/ALZ-21-e14402-g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/944a/11848385/3302a7a5c7d0/ALZ-21-e14402-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/944a/11848385/18a7b488fd69/ALZ-21-e14402-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/944a/11848385/7438df59ada4/ALZ-21-e14402-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/944a/11848385/f1bd1c1440ef/ALZ-21-e14402-g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/944a/11848385/7a0b04df7431/ALZ-21-e14402-g002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/944a/11848385/7438df59ada4/ALZ-21-e14402-g003.jpg

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