Peripheral Neutrophils-Derived Matrix Metallopeptidase-9 Induces Postoperative Cognitive Dysfunction in Aged Mice

Lili Huang; Weitian Tian; Xuemei Chen; Huan Xu; Wanbing Dai; Yizhe Zhang; Xiaodan Wu; Weifeng Yu; Jie Tian; Diansan Su

doi:10.3389/fnagi.2022.683295

Peripheral Neutrophils-Derived Matrix Metallopeptidase-9 Induces Postoperative Cognitive Dysfunction in Aged Mice

Front Aging Neurosci. 2022 Feb 22:14:683295. doi: 10.3389/fnagi.2022.683295. eCollection 2022.

Authors

Lili Huang¹, Weitian Tian¹, Xuemei Chen¹, Huan Xu², Wanbing Dai¹, Yizhe Zhang¹, Xiaodan Wu³, Weifeng Yu¹, Jie Tian¹, Diansan Su¹

Affiliations

¹ Department of Anesthesiology, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China.
² Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University, Shanghai, China.
³ Department of Anesthesiology, Shengli Clinical Medical College, Fujian Provincial Hospital, Fujian Medical University, Fuzhou, China.

Abstract

Background: Aging is one of the most important risk factors of postoperative cognitive dysfunction (POCD); however, the mechanisms are still not completely understood. In this study, we explore the roles of matrix metalloproteinase-9 (MMP-9) in aged mice with POCD.

Methods: Appendectomy was performed in 18-month-old C57BL/6 and MMP-9^-/- mice under anesthesia to establish the POCD model. Learning and memory were assessed using the Morris water maze (MWM) or Barnes maze. Protein expression of MMP-9 was measured by Western blotting or enzyme-linked immunosorbent assay (ELISA). To explore the role of neutrophils-derived MMP-9 in POCD, we treated mice with anti-Gr-1 monoclonal antibody to deplete peripheral neutrophils. And the percentage of neutrophils and other leukocytes were detected by flow cytometry. We further used sodium fluorescein (NaFlu) to evaluate the blood-brain barrier (BBB) permeability.

Results: The spatial learning and memory ability was injured, and expression of MMP-9 increased in both plasma and the hippocampus after anesthesia/surgery. However, cognitive dysfunction was alleviated in both MMP-9^-/- and peripheral neutrophils-depleted mice. The permeability of BBB was increased after anesthesia/surgery while recused by anti-Gr-1 antibody administration.

Conclusion: These findings suggest that peripheral neutrophils-derived MMP-9 could lead to POCD of aged mice through increasing the BBB permeability.

Keywords: anesthesia and surgery; blood–brain barrier; matrix metallopeptidase- 9; neutrophils; postoperative cognitive dysfunction.