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journal article·2026-06-22Open access

Lilrb4a Suppression Reprograms Microglia to Mitigate APOE4‐Associated Amyloid Plaques and Cerebral Amyloid Angiopathy in Association With a PPAR‐Linked Pro‐Clearance State

Changxu Nie, Ruixi Yang, Xiaotong Wang, Ping Jia, Xueqi Zhang, Yaqi Dai, Xue Bai, Sijia Duan, Yufeng Li, Peng Zheng, Xin Tian, Li Jiang, Chao Wang

Advanced Science
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Abstract

ABSTRACT The mouse gene Lilrb4a , an ortholog of human leukocyte immunoglobulin‐like receptor B4 ( LILRB4 ), is markedly upregulated in microglia in Alzheimer's disease models and has been implicated in Apolipoprotein E (APOE)‐related signaling. However, its contribution to amyloid pathology under an APOE4 background remains unclear. Here, 5xFAD mice carrying human APOE4 were used to assess the impact of Lilrb4a reduction by genetic deletion or antisense oligonucleotide treatment. Both approaches significantly reduced cortical amyloid plaque burden and APOE4‐associated cerebral amyloid angiopathy without altering amyloid‐β (Aβ) production. Bulk RNA sequencing identified enrichment of peroxisome proliferator‐activated receptor (PPAR)‐related and broader metabolic pathways in Lilrb4a ‐deficient mice. Consistently, biochemical analyses showed reduced p‐SHP‐2, NF‐κB‐p65, and p‐STAT1, increased p‐STAT3, and induction of anti‐inflammatory and clearance‐associated effectors, including Arg‐1, TGF‐β, and Cyp2e1. In primary microglia, pharmacological interrogation supported a functional contribution of PPAR‐γ signaling to the enhanced Aβ uptake and degradation associated with Lilrb4a suppression, whereas PPAR‐γ agonism recapitulated key pro‐clearance phenotypes in vitro and attenuated amyloid pathology in vivo. Together, these data support Lilrb4a as an APOE4‐associated microglial checkpoint candidate linked to impaired amyloid clearance and identify a PPAR‐linked pro‐clearance program as a potential downstream component of this response.
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Research context

OpenAlex topics: Alzheimer's disease research and treatments · Neuroinflammation and Neurodegeneration Mechanisms · Neurogenesis and neuroplasticity mechanisms

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Affiliations

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

Guangzhou National Laboratory Graduate School of Guangzhou Medical University Guangzhou Guangdong China

Department of Neurology The First Affiliated Hospital of Chongqing Medical University Jinfeng Laboratory Chongqing China

Department of Geriatrics Laboratory of Research and Translation for Geriatric Diseases Department of Neurology The First Affiliated Hospital of Chongqing Medical University The First Affiliated Hospital of Chongqing Medical University Chongqing Key Laboratory of Major Neurological and Mental Disorders Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education) Chongqing Medical University Chongqing China

Department of Neurosurgery The First Affiliated Hospital of Chongqing Medical University Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education) Chongqing Medical University Chongqing China

Funding

National Natural Science Foundation of China · National Outstanding Youth Science Fund Project of National Natural Science Foundation of China · Key Technologies Research and Development Program

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