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阿尔茨海默病风险基因SORL1促进人类小胶质细胞对促炎刺激的反应性。

Alzheimer's Disease Risk Gene SORL1 Promotes Receptiveness of Human Microglia to Pro-Inflammatory Stimuli.

作者信息

Ovesen Peter Lund, Juul-Madsen Kristian, Telugu Narasimha S, Schmidt Vanessa, Frahm Silke, Radbruch Helena, Louth Emma Louise, Korshøj Anders Rosendal, Heppner Frank L, Diecke Sebastian, Kettenmann Helmut, Willnow Thomas E

机构信息

Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.

Department of Biomedicine, Aarhus University, Aarhus, Denmark.

出版信息

Glia. 2025 Apr;73(4):857-872. doi: 10.1002/glia.24659. Epub 2024 Dec 17.

DOI:10.1002/glia.24659
PMID:39688327
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11845846/
Abstract

Sorting protein-related receptor containing class A repeats (SORLA) is an intracellular trafficking receptor encoded by the Alzheimer's disease (AD) gene SORL1 (sortilin-related receptor 1). Recent findings argue that altered expression in microglia may underlie the genome-wide risk of AD seen with some SORL1 gene variants, however, the functional significance of the receptor in microglia remains poorly explained. Using unbiased omics and targeted functional analyses in iPSC-based human microglia, we identified a crucial role for SORLA in sensitizing microglia to pro-inflammatory stimuli. We show that SORLA acts as a sorting factor for the pattern recognition receptor CD14, directing CD14 exposure on the cell surface and priming microglia to stimulation by pro-inflammatory factors. Loss of SORLA in gene-targeted microglia impairs proper CD14 sorting and blunts pro-inflammatory responses. Our studies indicate an important role for SORLA in shaping the inflammatory brain milieu, a biological process important to local immune responses in AD.

摘要

含A类重复序列的分选蛋白相关受体（SORLA）是一种由阿尔茨海默病（AD）基因SORL1（sortilin相关受体1）编码的细胞内运输受体。最近的研究结果表明，小胶质细胞中表达的改变可能是某些SORL1基因变异所导致的全基因组AD风险的基础，然而，该受体在小胶质细胞中的功能意义仍未得到充分解释。通过基于诱导多能干细胞的人类小胶质细胞进行无偏组学和靶向功能分析，我们发现SORLA在使小胶质细胞对促炎刺激敏感方面起着关键作用。我们表明，SORLA作为模式识别受体CD14的分选因子，指导CD14在细胞表面的暴露，并使小胶质细胞对促炎因子的刺激产生反应。基因靶向小胶质细胞中SORLA的缺失会损害CD14的正常分选，并减弱促炎反应。我们的研究表明，SORLA在塑造炎症性脑环境中起着重要作用，这是AD局部免疫反应中的一个重要生物学过程。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a762/11845846/d542dc55cda2/GLIA-73-857-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a762/11845846/e87a2ee1eb76/GLIA-73-857-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a762/11845846/f0ce7b321cd3/GLIA-73-857-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a762/11845846/24bf0768ceeb/GLIA-73-857-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a762/11845846/c0f743a7ea24/GLIA-73-857-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a762/11845846/bca0ab76cd56/GLIA-73-857-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a762/11845846/d542dc55cda2/GLIA-73-857-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a762/11845846/e87a2ee1eb76/GLIA-73-857-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a762/11845846/a24ef50684a6/GLIA-73-857-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a762/11845846/f0ce7b321cd3/GLIA-73-857-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a762/11845846/24bf0768ceeb/GLIA-73-857-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a762/11845846/c0f743a7ea24/GLIA-73-857-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a762/11845846/bca0ab76cd56/GLIA-73-857-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a762/11845846/d542dc55cda2/GLIA-73-857-g003.jpg

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本文引用的文献

1
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FEBS J. 2024 Aug;291(15):3499-3520. doi: 10.1111/febs.17150. Epub 2024 May 7.
2
Xenografted human microglia display diverse transcriptomic states in response to Alzheimer's disease-related amyloid-β pathology.人源异种移植物小胶质细胞在应对与阿尔茨海默病相关的淀粉样蛋白-β病理时表现出多样化的转录组状态。
Nat Neurosci. 2024 May;27(5):886-900. doi: 10.1038/s41593-024-01600-y. Epub 2024 Mar 27.
3
Differential effects of deficiency on the endo-lysosomal network in human neurons and microglia.
阿尔茨海默病基因调节人类小胶质细胞中的溶酶体功能。
bioRxiv. 2025 Jan 7:2024.06.25.600648. doi: 10.1101/2024.06.25.600648.
缺乏症对人类神经元和小神经胶质细胞内溶酶体网络的差异影响。
Philos Trans R Soc Lond B Biol Sci. 2024 Apr 8;379(1899):20220389. doi: 10.1098/rstb.2022.0389. Epub 2024 Feb 19.
4
Proteomic and transcriptomic profiling of brainstem, cerebellum and olfactory tissues in early- and late-phase COVID-19.新冠病毒感染早、晚期患者脑干、小脑和嗅组织的蛋白质组学和转录组学分析。
Nat Neurosci. 2024 Mar;27(3):409-420. doi: 10.1038/s41593-024-01573-y. Epub 2024 Feb 16.
5
Amyloid-β aggregates activate peripheral monocytes in mild cognitive impairment.淀粉样蛋白-β聚集物在轻度认知障碍中激活外周单核细胞。
Nat Commun. 2024 Feb 9;15(1):1224. doi: 10.1038/s41467-024-45627-y.
6
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7
ASSURED-optimized CRISPR protocol for knockout/SNP knockin in hiPSCs.ASSURED-优化的 CRISPR 方案用于 hiPSCs 的基因敲除/SNP 敲入。
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8
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