CXCL16-driven neutrophil extracellular traps promote osteoporosis in APP/PS1 mice by disrupting bone remodeling.

Authors

Rui Chen, Xiao Sun, Tianyi Wu, Lide Tao, Leyu Zhao, Xianggu Zhong, Qi Zhang, Qi Yan, Shunyi Lu, Zhuorun Song, Dawei Song, Luyang Li, Junjie Niu, Huilin Yang, Yun Teng, Jun Zou

Published in

Bone. Pages 118126. Oct 08, 2026. Epub Oct 08, 2026.

Abstract

Patients with Alzheimer's disease (AD) often exhibit abnormal bone loss alongside cognitive impairment. However, the mechanisms linking these two conditions remain insufficiently understood. We first employed amyloid precursor protein/presenilin 1 (APP/PS1) mice as the experimental model and demonstrated that they exhibit significant bone loss concurrent with cognitive impairment. Subsequently, we analyzed public datasets for AD and osteoporosis (OP) and identified CXC chemokine ligand 16 (CXCL16) as a shared hub gene between the two diseases. Transcriptomic sequencing further showed increased CXCL16 expression in the femoral tissue of APP/PS1 mice. Immunoblot analysis of brain and bone tissues, together with serum enzyme-linked immunosorbent assay (ELISA), verified the systemic elevation of CXCL16. These findings suggest that CXCL16 may link cognitive impairment with bone loss in APP/PS1 mice. In vitro experiments showed that CXCL16 did not directly affect the differentiation of bone marrow mesenchymal stem cells or bone marrow-derived macrophages. Instead, CXCL16 acted through neutrophils by promoting their migration and potentiating PMA-stimulated neutrophil extracellular trap (NET) formation. Conditioned medium from NET-producing neutrophils inhibited osteogenic differentiation and promoted osteoclastogenesis. In APP/PS1 mice, antagonism of CXCR6, the cognate receptor for CXCL16, with ML339 improved trabecular bone microarchitecture and osteogenic activity and alleviated cognitive impairment. Degradation of NETs with deoxyribonuclease I (DNase I) produced similar effects. Collectively, these results implicate CXCL16-associated enhancement of NET formation in AD-related skeletal deterioration and highlight the CXCL16-NETs pathway as a possible intervention target for maintaining bone homeostasis.

PMID:
42849643
Bibliographic data and abstract were imported from PubMed on 09 Oct 2026.

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