Department of Neurobiology and Behavior, University of California, Irvine, Irvine, United States; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, United States; UCI Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, United States; Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, United States
Alberto Granzotto
Department of Neurobiology and Behavior, University of California, Irvine, Irvine, United States; Center for Advanced Sciences and Technology (CAST), University "G. d'Annunzio" of Chieti-Pescara, Chieti, Italy; Department of Neuroscience, Imaging and Clinical Sciences, University G d'Annunzio of Chieti-Pescara, Chieti, Italy
You Jung Kang
Department of Mechanical Engineering and Engineering Science, University of North Carolina, Charlotte, United States
Jean Paul Chadarevian
Department of Neurobiology and Behavior, University of California, Irvine, Irvine, United States
Sunil Gandhi
Department of Neurobiology and Behavior, University of California, Irvine, Irvine, United States
Ian Parker
Department of Physiology and Biophysics, University of California, Irvine, Irvine, United States; Department of Neurobiology and Behavior, University of California, Irvine, Irvine, United States
Department of Neurobiology and Behavior, University of California, Irvine, Irvine, United States
Hansang Cho
Institute of Quantum Biophysics, Department of Biophysics, Dept of Intelligent Precision Healthcare Convergence, Sungkyunkwan University, Gyeonggi-do, Republic of Korea
Stefano L Sensi
Center for Advanced Sciences and Technology (CAST), University "G. d'Annunzio" of Chieti-Pescara, Chieti, Italy; Department of Neuroscience, Imaging and Clinical Sciences, University G d'Annunzio of Chieti-Pescara, Chieti, Italy
Department of Physiology and Biophysics, University of California, Irvine, Irvine, United States; Institute for Immunology, University of California, Irvine, Irvine, United States
Department of Neurobiology and Behavior, University of California, Irvine, Irvine, United States; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, United States; UCI Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, United States; Institute for Immunology, University of California, Irvine, Irvine, United States
Department of Physiology and Biophysics, University of California, Irvine, Irvine, United States; Institute for Immunology, University of California, Irvine, Irvine, United States
The membrane protein TREM2 (Triggering Receptor Expressed on Myeloid cells 2) regulates key microglial functions including phagocytosis and chemotaxis. Loss-of-function variants of TREM2 are associated with increased risk of Alzheimer’s disease (AD). Because abnormalities in Ca2+ signaling have been observed in several AD models, we investigated TREM2 regulation of Ca2+ signaling in human induced pluripotent stem cell-derived microglia (iPSC-microglia) with genetic deletion of TREM2. We found that iPSC-microglia lacking TREM2 (TREM2 KO) show exaggerated Ca2+ signals in response to purinergic agonists, such as ADP, that shape microglial injury responses. This ADP hypersensitivity, driven by increased expression of P2Y12 and P2Y13 receptors, results in greater release of Ca2+ from the endoplasmic reticulum stores, which triggers sustained Ca2+ influx through Orai channels and alters cell motility in TREM2 KO microglia. Using iPSC-microglia expressing the genetically encoded Ca2+ probe, Salsa6f, we found that cytosolic Ca2+ tunes motility to a greater extent in TREM2 KO microglia. Despite showing greater overall displacement, TREM2 KO microglia exhibit reduced directional chemotaxis along ADP gradients. Accordingly, the chemotactic defect in TREM2 KO microglia was rescued by reducing cytosolic Ca2+ using a P2Y12 receptor antagonist. Our results show that loss of TREM2 confers a defect in microglial Ca2+ response to purinergic signals, suggesting a window of Ca2+ signaling for optimal microglial motility.
