{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T11:52:05Z","timestamp":1791373925968,"version":"4.3.1"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Human leukocyte antigen class II (HLA-II) genes mark several microglial states in Alzheimer\u2019s disease, but it remains unclear how their average transcription relates to tau measured in the same brain region.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We used a locked 13-gene HLA-II panel selected by biological function, cross-cohort detection, and variance, without considering effect estimates. The primary analysis was conducted using the Seattle Alzheimer\u2019s Disease Brain Cell Atlas (SEA-AD): 361 donor-region observations from 79 donors across 6 cortical regions were modeled with within-donor pathology decomposition, region fixed effects, and a donor random intercept. A paired entorhinal-versus-somatosensory analysis in GSE160936 (11 donors) provided additional support for our findings. Sensitivity analyses addressed amyloid-\u03b2, RNA quality, neuronal-nuclei enrichment, microglial-state composition, published state annotations, alternative panels, region omission, and assay modality. Public human induced pluripotent stem cell (iPSC)-microglia data were used to provide a distinct tau-exposure context.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In the SEA-AD study, a higher local AT8-positive area within a donor was associated with a lower expanded HLA-II score (\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u202f=\u202f\u22120.174, 95% confidence interval [CI]: \u22120.297 to \u22120.052;\n                      <jats:italic>p<\/jats:italic>\n                      \u202f=\u202f0.005). The estimate remained negative after adjusting for local amyloid-\u03b2, RNA integrity number, and the NeuN-positive fluorescence-activated nuclei sorting (FANS) fraction (\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u202f=\u202f\u22120.167, 95% CI: \u22120.289 to \u22120.045;\n                      <jats:italic>p<\/jats:italic>\n                      \u202f=\u202f0.007). This result was consistent after adjusting for the proportion of a published Damage-Associated Microglia (DAM)-enriched state. A formal tau-minus-amyloid-\u03b2 contrast was not significant. In GSE160936, the expanded-panel pTau coefficient was negative (\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u202f=\u202f\u22120.533); however, the primary exact test was not significant after the two-test correction (\n                      <jats:italic>p<\/jats:italic>\n                      \u202f=\u202f0.083;\n                      <jats:italic>q<\/jats:italic>\n                      \u202f=\u202f0.166). Fibrillar tau exposure lowered the score derived from the 12 detectable panel genes in iPSC-microglia (difference\u202f=\u202f\u22121.343; exact\n                      <jats:italic>p<\/jats:italic>\n                      \u202f=\u202f0.029).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>In a larger multi-region cohort and a smaller paired cohort, we observed that regional tau burden was associated with lower levels of pooled microglial HLA-II transcription. The association was not explained solely by the measured proportion of the DAM-like state. However, the data do not establish tau specificity, direct suppression, protein-level antigen presentation, or a causal mechanism.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnins.2026.1979981","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T11:11:21Z","timestamp":1791371481000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Regional tau burden tracks with lower microglial HLA class II transcription in the human brain"],"prefix":"10.3389","volume":"20","author":[{"given":"Fan","family":"Li","sequence":"first","affiliation":[{"name":"Department of Neurology, The Second Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suqin","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Second Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Second Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Second Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianghua","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, The Second Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feifei","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, The Second Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Second Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,7]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1488382","DOI":"10.3389\/fnins.2024.1488382","article-title":"Myeloid antigen-presenting cells in neurodegenerative diseases: a focus on classical and non-classical MHC molecules","volume":"18","author":"Afify","year":"2024","journal-title":"Front. 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