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在阿尔茨海默病转基因模型中，PU.1决定β-淀粉样蛋白诱导的小胶质细胞中TREM2表达上调。

PU.1 dictates β-amyloid-induced TREM2 expression upregulation in microglia in a transgenic model of Alzheimer's disease.

作者信息

Wei Zhen, Pan Xiaodong, Cui Xiaoli, Zhang Jing, Dai Xiaoman, Zeng Yuqi, Chen Xiaochun

机构信息

Department of Neurology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China.

Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, China.

出版信息

Front Aging Neurosci. 2025 May 1;17:1537388. doi: 10.3389/fnagi.2025.1537388. eCollection 2025.

DOI:10.3389/fnagi.2025.1537388
PMID:40376093
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12078285/
Abstract

INTRODUCTION: Microglial dysfunction is characteristic of Alzheimer's disease (AD), with triggering receptor expressed on myeloid cells 2 (TREM2) and transcription factor PU.1 playing crucial roles. However, the relationship between TREM2 and PU.1 remains unclear. METHODS: We investigated TREM2 and PU.1 expression patterns in the 5×FAD mouse AD model. Experimental approaches included quantitative PCR, western blotting, immunofluorescence staining, chromatin immunoprecipitation, and luciferase reporter assays to examine the interaction between PU.1 and TREM2. The phagocytic function of microglial cells was evaluated using Aβ42 and Nile red fluorescent microsphere phagocytosis assays. RESULTS: TREM2 and PU.1 expression significantly correlated with brain β-amyloid (β) deposition. PU.1 directly interacted with the TREM2 promoter region, promoting its transcription and potently impacting microglial phagocytosis. PU.1 overexpression amplified TREM2 expression, while PU.1 knockdown reduced it. DISCUSSION: Our findings reveal a novel regulatory mechanism where PU.1 directly modulates TREM2 transcription in activated microglia during AD progression. These insights highlight the potential of TREM2 and PU.1 as therapeutic targets in AD treatment.

摘要

引言：小胶质细胞功能障碍是阿尔茨海默病（AD）的特征，髓系细胞触发受体2（TREM2）和转录因子PU.1发挥着关键作用。然而，TREM2与PU.1之间的关系仍不清楚。 方法：我们在5×FAD小鼠AD模型中研究了TREM2和PU.1的表达模式。实验方法包括定量PCR、蛋白质免疫印迹、免疫荧光染色、染色质免疫沉淀和荧光素酶报告基因检测，以检测PU.1与TREM2之间的相互作用。使用Aβ42和尼罗红荧光微球吞噬试验评估小胶质细胞的吞噬功能。 结果：TREM2和PU.1的表达与脑β-淀粉样蛋白（β）沉积显著相关。PU.1直接与TREM2启动子区域相互作用，促进其转录，并对小胶质细胞吞噬作用产生显著影响。PU.1过表达增强了TREM2的表达，而PU.1敲低则降低了TREM2的表达。 讨论：我们的研究结果揭示了一种新的调节机制，即在AD进展过程中，PU.1直接调节活化小胶质细胞中TREM2的转录。这些见解突出了TREM2和PU.1作为AD治疗靶点的潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1e5/12078285/70b1791cb49c/fnagi-17-1537388-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1e5/12078285/e132f428ca4d/fnagi-17-1537388-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1e5/12078285/61734373dc2f/fnagi-17-1537388-g002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1e5/12078285/ca0aa5e8f3af/fnagi-17-1537388-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1e5/12078285/4cecad3108cf/fnagi-17-1537388-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1e5/12078285/6419ce862e91/fnagi-17-1537388-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1e5/12078285/dc825da739b6/fnagi-17-1537388-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1e5/12078285/70b1791cb49c/fnagi-17-1537388-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1e5/12078285/e132f428ca4d/fnagi-17-1537388-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1e5/12078285/61734373dc2f/fnagi-17-1537388-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1e5/12078285/12131225fc97/fnagi-17-1537388-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1e5/12078285/4f530e7357e5/fnagi-17-1537388-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1e5/12078285/ca0aa5e8f3af/fnagi-17-1537388-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1e5/12078285/4cecad3108cf/fnagi-17-1537388-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1e5/12078285/6419ce862e91/fnagi-17-1537388-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1e5/12078285/dc825da739b6/fnagi-17-1537388-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f1e5/12078285/70b1791cb49c/fnagi-17-1537388-g009.jpg

相似文献

[1]
PU.1 dictates β-amyloid-induced TREM2 expression upregulation in microglia in a transgenic model of Alzheimer's disease.

Front Aging Neurosci. 2025-5-1

[2]
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[3]
Microglial Trem2 induces synaptic impairment at early stage and prevents amyloidosis at late stage in APP/PS1 mice.

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[4]
Discovery and engineering of an anti-TREM2 antibody to promote amyloid plaque clearance by microglia in 5XFAD mice.

MAbs. 2022

[5]
Upregulation of TREM2 ameliorates neuropathology and rescues spatial cognitive impairment in a transgenic mouse model of Alzheimer's disease.

Neuropsychopharmacology. 2014-12

[6]
BAC Transgenic Expression of Human TREM2-R47H Remodels Amyloid Plaques but Unable to Reprogram Plaque-associated Microglial Reactivity in 5xFAD Mice.

bioRxiv. 2023-8-5

[7]
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Nutrients. 2024-10-20

[8]
Amyloid-beta modulates microglial responses by binding to the triggering receptor expressed on myeloid cells 2 (TREM2).

Mol Neurodegener. 2018-3-27

[9]
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[10]
TREM2 Overexpression has No Improvement on Neuropathology and Cognitive Impairment in Aging APPswe/PS1dE9 Mice.

Mol Neurobiol. 2017-3

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SHIP1 modulation and proteome characterization of microglia.

J Proteomics. 2024-6-30

[2]
MHC-I in the hippocampus promotes comorbid depressive symptoms in bone cancer pain via the upregulation of microglial TREM2/DAP12 signaling.

Behav Brain Res. 2024-3-12

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Brain Res. 2024-1-1

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J Biol Chem. 2023-5

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