{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T14:18:32Z","timestamp":1791555512743,"version":"4.3.4"},"reference-count":62,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T00:00:00Z","timestamp":1746748800000},"content-version":"vor","delay-in-days":8,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T00:00:00Z","timestamp":1746057600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["RF1AG074566"],"award-info":[{"award-number":["RF1AG074566"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp;amp; Dementia"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>BACKGROUND<\/jats:title>\n                    <jats:p>Phospholipase C gamma 2 (PLCG2) is an intracellular effector of microglial cell surface receptors, including triggering receptor expressed on myeloid cells 2 (TREM2). Variants which alter PLCG2 activity impact Alzheimer's disease (AD) risk, but the effects of PLCG2 deficiency in AD remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>5xFAD mice were crossed with PLCG2\u2010 and TREM2\u2010deficient mice to assess the role of PLCG2 in response to amyloid pathology. Human bulk RNA\u2010sequencing data were used to validate findings in AD patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      In 5xFAD mice, the absence of PLCG2 resulted in reduced TREM2 expression and impaired microglial associations with amyloid beta plaques. Transcriptomic analysis revealed perturbations in immune\u2010related pathways shared between PLCG2 and TREM2 deficiencies, as well as distinct differences. Human transcriptomics revealed positive correlations between\n                      <jats:italic>PLCG2<\/jats:italic>\n                      and\n                      <jats:italic>TREM2<\/jats:italic>\n                      independent of pathological scores.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>PLCG2 is a critical component of TREM2 signal transduction and may play an upstream role in TREM2 regulation. These findings clarify the mechanisms of risk and protective PLCG2 variants.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>The role of phospholipase C gamma 2 (PLCG2) deficiency in response to amyloid beta (A\u03b2) pathology was investigated in 5xFAD mice and with human cortical transcriptomics.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>PLCG2 deficiency significantly reduces triggering receptor expressed on myeloid cells 2 (TREM2) expression, while TREM2 deficiency increases PLCG2 expression.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            <jats:italic>PLCG2<\/jats:italic>\n                            expression predicts\n                            <jats:italic>TREM2<\/jats:italic>\n                            expression in human cortex independent of pathology.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>PLCG2 and TREM2 deficiencies similarly impair microglial responses to A\u03b2 plaques, exacerbate neuronal pathology, and impair gene expression associated with immune responses.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>PLCG2 deficiency confers distinct transcriptional perturbations from TREM2 deficiency.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>PLCG2 may play an upstream role in the regulation of the TREM2\u2010mediated immune response.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.70231","type":"journal-article","created":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T23:20:40Z","timestamp":1746832840000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology"],"prefix":"10.1002","volume":"21","author":[{"given":"Evan J.","family":"Messenger","sequence":"first","affiliation":[{"name":"Stark Neuroscience Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sydney A.","family":"Baar","sequence":"additional","affiliation":[{"name":"Stark Neuroscience Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Logan M.","family":"Bedford","sequence":"additional","affiliation":[{"name":"Stark Neuroscience Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andy P.","family":"Tsai","sequence":"additional","affiliation":[{"name":"Stark Neuroscience Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter Bor\u2010Chian","family":"Lin","sequence":"additional","affiliation":[{"name":"Stark Neuroscience Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chloe A.","family":"Ferguson","sequence":"additional","affiliation":[{"name":"Stark Neuroscience Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guixiang","family":"Xu","sequence":"additional","affiliation":[{"name":"Stark Neuroscience Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail","family":"Wallace","sequence":"additional","affiliation":[{"name":"Stark Neuroscience Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary E.","family":"Landreth","sequence":"additional","affiliation":[{"name":"Stark Neuroscience Indiana University School of Medicine  Indianapolis Indiana USA"},{"name":"Department of Anatomy, Cell Biology &amp; 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