TY  - JOUR
AU  - Ovesen, Peter Lund
AU  - Juul-Madsen, Kristian
AU  - Telugu, Narasimha S
AU  - Schmidt, Vanessa
AU  - Frahm, Silke
AU  - Radbruch, Helena
AU  - Louth, Emma Louise
AU  - Korshøj, Anders Rosendal
AU  - Heppner, Frank L
AU  - Diecke, Sebastian
AU  - Kettenmann, Helmut
AU  - Willnow, Thomas E
TI  - Alzheimer's Disease Risk Gene SORL1 Promotes Receptiveness of Human Microglia to Pro-Inflammatory Stimuli.
JO  - Glia
VL  - 73
IS  - 4
SN  - 0894-1491
CY  - Bognor Regis [u.a.]
PB  - Wiley-Liss
M1  - DZNE-2025-00335
SP  - 857 - 872
PY  - 2025
AB  - 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.
KW  - Humans
KW  - Microglia: metabolism
KW  - Alzheimer Disease: genetics
KW  - Alzheimer Disease: metabolism
KW  - Alzheimer Disease: pathology
KW  - LDL-Receptor Related Proteins: genetics
KW  - LDL-Receptor Related Proteins: metabolism
KW  - Membrane Transport Proteins: genetics
KW  - Membrane Transport Proteins: metabolism
KW  - Lipopolysaccharide Receptors: metabolism
KW  - Lipopolysaccharide Receptors: genetics
KW  - Induced Pluripotent Stem Cells: metabolism
KW  - Inflammation: metabolism
KW  - Inflammation: genetics
KW  - Alzheimer's disease (Other)
KW  - SORLA (Other)
KW  - VPS10P domain receptors (Other)
KW  - brain inflammation (Other)
KW  - microglia (Other)
KW  - SORL1 protein, human (NLM Chemicals)
KW  - LDL-Receptor Related Proteins (NLM Chemicals)
KW  - Membrane Transport Proteins (NLM Chemicals)
KW  - Lipopolysaccharide Receptors (NLM Chemicals)
KW  - CD14 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39688327
C2  - pmc:PMC11845846
DO  - DOI:10.1002/glia.24659
UR  - https://pub.dzne.de/record/276822
ER  -