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However, its contribution to amyloid pathology under an APOE4 background remains unclear. Here, 5xFAD mice carrying human\n                    <jats:italic>APOE4<\/jats:italic>\n                    were used to assess the impact of\n                    <jats:italic>Lilrb4a<\/jats:italic>\n                    reduction by genetic deletion or antisense oligonucleotide treatment. Both approaches significantly reduced cortical amyloid plaque burden and APOE4\u2010associated cerebral amyloid angiopathy without altering amyloid\u2010\u03b2 (A\u03b2) production. Bulk RNA sequencing identified enrichment of peroxisome proliferator\u2010activated receptor (PPAR)\u2010related and broader metabolic pathways in\n                    <jats:italic>Lilrb4a<\/jats:italic>\n                    \u2010deficient mice. Consistently, biochemical analyses showed reduced p\u2010SHP\u20102, NF\u2010\u03baB\u2010p65, and p\u2010STAT1, increased p\u2010STAT3, and induction of anti\u2010inflammatory and clearance\u2010associated effectors, including Arg\u20101, TGF\u2010\u03b2, and Cyp2e1. In primary microglia, pharmacological interrogation supported a functional contribution of PPAR\u2010\u03b3 signaling to the enhanced A\u03b2 uptake and degradation associated with\n                    <jats:italic>Lilrb4a<\/jats:italic>\n                    suppression, whereas PPAR\u2010\u03b3 agonism recapitulated key pro\u2010clearance phenotypes in vitro\u00a0and attenuated amyloid pathology in vivo. Together, these data support Lilrb4a as an APOE4\u2010associated microglial checkpoint candidate linked to impaired amyloid clearance and identify a PPAR\u2010linked pro\u2010clearance program as a potential downstream component of this response.\n                  <\/jats:p>","DOI":"10.1002\/advs.202524167","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T19:46:28Z","timestamp":1782157588000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lilrb4a Suppression Reprograms Microglia to Mitigate APOE4\u2010Associated Amyloid Plaques and Cerebral Amyloid Angiopathy in Association With a PPAR\u2010Linked Pro\u2010Clearance State"],"prefix":"10.1002","volume":"13","author":[{"given":"Changxu","family":"Nie","sequence":"first","affiliation":[{"name":"Department of Psychiatry The First Affiliated Hospital of Chongqing Medical University Department of Neurobiology School of Basic Medical Sciences Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education) Chongqing Medical University  Chongqing China"},{"name":"Guangzhou National Laboratory Graduate School of Guangzhou Medical University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruixi","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Psychiatry The First Affiliated Hospital of Chongqing Medical University Department of Neurobiology School of Basic Medical Sciences Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education) Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaotong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Psychiatry The First Affiliated Hospital of Chongqing Medical University Department of Neurobiology School of Basic Medical Sciences Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education) Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Psychiatry The First Affiliated Hospital of Chongqing Medical University Department of Neurobiology School of Basic Medical Sciences Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education) Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueqi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Psychiatry The First Affiliated Hospital of Chongqing Medical University Department of Neurobiology School of Basic Medical Sciences Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education) Chongqing Medical University  Chongqing 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Affiliated Hospital of Chongqing Medical University Department of Neurobiology School of Basic Medical Sciences Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education) Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufeng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Psychiatry The First Affiliated Hospital of Chongqing Medical University Department of Neurobiology School of Basic Medical Sciences Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education) Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Neurology The First Affiliated Hospital of Chongqing Medical University Jinfeng Laboratory  Chongqing 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