{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T14:48:06Z","timestamp":1776437286030,"version":"3.51.2"},"reference-count":60,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T00:00:00Z","timestamp":1761091200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T00:00:00Z","timestamp":1761091200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100020595","name":"National Science and Technology Council","doi-asserted-by":"publisher","award":["MOST 113\u20102313\u2010B\u2010005\u2010008"],"award-info":[{"award-number":["MOST 113\u20102313\u2010B\u2010005\u2010008"]}],"id":[{"id":"10.13039\/100020595","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Glia"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are age\u2010related disorders with similar pathological features, particularly insulin resistance and chronic inflammation. However, the primary drivers of insulin resistance in the AD brain remain debated. Although astrocytes and their metabolic functions have been increasingly implicated in AD, their specific role in brain insulin resistance is still unclear. In this study, we excluded peripheral metabolic confounders and focused on the alterations during a narrow time window surrounding amyloid\u2010\u03b2 (A\u03b2) plaque deposition in J20 mice. As A\u03b2 pathology progressed, we observed a reduction in astrocyte numbers with increased morphological complexity. Furthermore, transcriptomic profiling demonstrated altered gene expression at synaptic, glial, and metabolic levels, along with a general suppression of insulin signaling pathways that indicated insulin resistance. Notably, we found a significant downregulation of serum and glucocorticoid\u2010inducible kinase 1 (SGK1) and upregulation of insulin receptor substrate 2 (IRS2) expression, which diverged from the classic pattern observed in peripheral insulin resistance. We also detected a contradictory cytokine pattern in T\u2010helper 17, where interleukin (IL)\u20106 and IL\u201017 levels were decreased in the hippocampus but elevated in the serum. This opposing trajectory suggests that astrocyte dysfunction and SGK1 downregulation have a critical role in immune signaling imbalance. Taken together, these findings highlight astrocyte depletion and\/or dysfunction as key drivers of brain\u2010specific insulin resistance and immune dysregulation in early AD, and that metabolic impairments in AD have a central nervous system\u2010specific nature distinct from that in T2DM.<\/jats:p>","DOI":"10.1002\/glia.70096","type":"journal-article","created":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T12:02:52Z","timestamp":1761134572000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Divergent\n                    <scp>CNS<\/scp>\n                    \u2013Peripheral Signaling Reflects Astrocyte Dysfunction and Contributes to Insulin Resistance in Early A\u03b2 Pathology"],"prefix":"10.1002","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-1871-0611","authenticated-orcid":false,"given":"Keng\u2010Ying","family":"Liao","sequence":"first","affiliation":[{"name":"Department of Veterinary Medicine National Chung Hsing University  Taichung Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8282-0306","authenticated-orcid":false,"given":"Yue\u2010Loong","family":"Hsin","sequence":"additional","affiliation":[{"name":"Department of Neurology Chung Shan Medical University and Chung Shan Medical University Hospital  Taichung Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6946-1153","authenticated-orcid":false,"given":"Wei\u2010Chi","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medicine National Chung Hsing University  Taichung Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6921-6737","authenticated-orcid":false,"given":"Chun\u2010Jung","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Medical Research Taichung Veterans General Hospital  Taichung Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5105-5285","authenticated-orcid":false,"given":"Wen\u2010Ying","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medicine National Chung Hsing University  Taichung 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