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Alzheimer's Disease Risk Gene SORL1 Promotes Receptiveness of Human Microglia to Pro‐Inflammatory Stimuli
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.
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Depletion of SORL1 may decrease the release of pro-inflammatory cytokines.
“Furthermore, the depletion of SORL1 may decrease the release of pro‐inflammatory cytokines either through conventional secretory routes from the TGN to the cell surface or by impairing LE, as observed in our study and others (Ovesen et al. 2024).”
From The Alzheimer's Disease Gene SORL1 Regulates Lysosome Function in Human Microglia (2025) · cites this paper as Ovesen et al. 2024
SORL1 and related pathways are novel therapeutic targets for AD.
“This data, along with recent work describing a role of SORLA in sorting neuroimmune receptors (Ovesen et al. 2024), adds to a growing body of work highlighting SORL1 and related pathways as novel therapeutic targets for ad.”
From The Alzheimer's Disease Gene SORL1 Regulates Lysosome Function in Human Microglia (2025) · cites this paper as Ovesen et al. 2024
SORL1 KO hMGLs show no difference in internalization of oligomeric Aβ compared to WT hMGLs.
“Interestingly, we did not observe a difference in internalization of oligomeric Aβ (Figure S4C), consistent with previous reports (Ovesen et al. 2024).”
From The Alzheimer's Disease Gene SORL1 Regulates Lysosome Function in Human Microglia (2025) · cites this paper as Ovesen et al. 2024
Multiple mechanisms may govern SORLA-mediated cytokine release in hMGLs.
“We also observed a blunted cytokine release in response to canonical pro‐inflammatory stimuli, LPS, and IFNγ, consistent with other recent reports in SORLA‐deficient hMGLs (Ovesen et al. 2024), suggesting that multiple mechanisms may govern SORLA‐mediated cytokine release in hMGLs.”
From The Alzheimer's Disease Gene SORL1 Regulates Lysosome Function in Human Microglia (2025) · cites this paper as Ovesen et al. 2024
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Citations
Cites
Innate immune activation in neurodegenerative disease
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“To validate the findings from the GO analyses, we tested the subcellular localization of SORLA in iMG using immunocytochemistry.”
An environment-dependent transcriptional network specifies human microglia identity
Gosselin, D., Skola, D., Coufal, N. G., Holtman, I. R., Schlachetzki, J. C. M., Sajti, E., Jaeger, B. N., O’Connor, C., Fitzpatrick, C., Pasillas, M. P., et al. (2017) · Science · doi:10.1126/science.aal3222 · Cited by 1,220 · cited 2×
“Prior single-cell sequencing studies have suggested that microglia is the cell type in the human brain with the highest levels of SORL1 transcript (Gosselin et al. 2017; Hansen, Hanson, and Sheng 2018).”
Alzheimer’s Disease Risk Gene CD33 Inhibits Microglial Uptake of Amyloid Beta
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Sorted by citations
Ren, F., Wei, J., Chen, Q., Hu, M., Yu, L., Mi, J., Zhou, X., Qin, D., Wu, J., & Wu, A. (2025) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2025.07.030 · Cited by 97
The Alzheimer's Disease Gene SORL1 Regulates Lysosome Function in Human Microglia
Mishra, S., Morshed, N., Sidhu, S. B., Kinoshita, C., Stevens, B., Jayadev, S., & Young, J. E. (2025) · Glia · doi:10.1002/glia.70009 · Cited by 31
Metadata
- Authors
- Ovesen, P. L., Juul‐Madsen, K., Telugu, N. S., Schmidt, V., Frahm, S., Radbruch, H., Louth, E. L., Korshøj, A. R., Heppner, F. L., Diecke, S., Kettenmann, H., & Willnow, T. E.
- Affiliations
- Max‐Delbrück‐Center for Molecular Medicine in the Helmholtz Association (MDC) Berlin Germany
- Technology Platform for Pluripotent Stem Cells, Max Delbrück Center for Molecular Medicine in the Helmholtz Association Berlin Germany
- Department of Neuropathology, Charité – Universitätsmedizin Berlin Corporate Member of Freie Universität Berlin and Humboldt‐Universität Zu Berlin Berlin Germany
- Department of Biomedicine Aarhus University Aarhus Denmark
- Department of Neurosurgery Aarhus University Hospital Aarhus Denmark
- Venue
- Glia
- Publisher
- Wiley
- Published
- 2024-12-17
- Volume
- 73
- Issue
- 4
- Pages
- 857-872
- ISSN
- 0894-1491
- 1098-1136
- PMC
- PMC11845846
- Cited by
- 14
- References
- 11
- Language
- en
- Funders
- Alzheimer Forschung Initiative (18003)
- Novo Nordisk Fonden (NNF18OC0033928)
- Lundbeck Foundation (R380‐2021‐1326)
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