Lilrb4a Suppression Reprograms Microglia to Mitigate APOE4-Associated Amyloid Plaques and Cerebral Amyloid Angiopathy in Association With a PPAR-Linked Pro-Clearance State.
Overview
- 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
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.
Reproduced under the paper's license (CC BY), from the paper cited above.
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Data
Datasets cited
- geo:GSE324957, at NCBI GEO; found in “Data Availability Statement”
Data Availability Statement
The RNA‐seq data generated in this study have been deposited in the GEO under accession number GSE324957 (https://
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
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Version 1, 27 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 13 authors, 7 keywords, 14 MeSH terms, 8 funders, 39 references, 2 RRIDs.
Cite
This paper
Nie, C., Yang, R., Wang, X., Jia, P., Zhang, X., Dai, Y., Bai, X., Duan, S., Li, Y., Zheng, P., Tian, X., Jiang, L., & Wang, C. (2026). Lilrb4a Suppression Reprograms Microglia to Mitigate APOE4-Associated Amyloid Plaques and Cerebral Amyloid Angiopathy in Association With a PPAR-Linked Pro-Clearance State. Advanced science (Weinheim, Baden-Wurttemberg, Germany), 13(50), e24167. https://
BibTeX
@article{nie2026lilrb4a,
author = {Nie, Changxu and Yang, Ruixi and Wang, Xiaotong and Jia, Ping and Zhang, Xueqi and Dai, Yaqi and Bai, Xue and Duan, Sijia and Li, Yufeng and Zheng, Peng and Tian, Xin and Jiang, Li and Wang, Chao},
title = {{Lilrb4a Suppression Reprograms Microglia to Mitigate APOE4-Associated Amyloid Plaques and Cerebral Amyloid Angiopathy in Association With a PPAR-Linked Pro-Clearance State}},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
year = {2026},
month = jun,
volume = {13},
number = {50},
pages = {e24167},
publisher = {Wiley},
issn = {2198-3844},
doi = {10.1002/
url = {https://
pmid = {42330346},
pmcid = {PMC13336908}
}
RIS
TY - JOUR
AU - Nie, Changxu
AU - Yang, Ruixi
AU - Wang, Xiaotong
AU - Jia, Ping
AU - Zhang, Xueqi
AU - Dai, Yaqi
AU - Bai, Xue
AU - Duan, Sijia
AU - Li, Yufeng
AU - Zheng, Peng
AU - Tian, Xin
AU - Jiang, Li
AU - Wang, Chao
TI - Lilrb4a Suppression Reprograms Microglia to Mitigate APOE4-Associated Amyloid Plaques and Cerebral Amyloid Angiopathy in Association With a PPAR-Linked Pro-Clearance State
T2 - Advanced science (Weinheim, Baden-Wurttemberg, Germany)
J2 - Adv Sci (Weinh)
PY - 2026
DA - 2026/
VL - 13
IS - 50
SP - e24167
SN - 2198-3844
PB - Wiley
DO - 10.1002/
UR - https://
LA - en
ER -
CSL-JSON
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"container-title": "Advanced science (Weinheim, Baden-Wurttemberg, Germany)",
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