Research Paper Volume 15, Issue 15 pp 7709—7726
Inhibition of BACE1 attenuates microglia-induced neuroinflammation after intracerebral hemorrhage by suppressing STAT3 activation
- 1 Department of Neurosurgery, Qilu Hospital, Shandong University, Jinan 250012, China
- 2 Department of Neurosurgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
- 3 Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China
Received: May 8, 2023 Accepted: July 10, 2023 Published: August 7, 2023
https://doi.org/10.18632/aging.204935How to Cite
Copyright: © 2023 Zhuang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Hematoma-induced neuroinflammation is the cause of poor prognosis in intracerebral hemorrhage (ICH); therefore, promoting blood clearance and blocking overactivated inflammation are rational approaches for ICH treatment. β-site amyloid precursor protein (APP) lyase-1 (BACE1) is a key molecule regulating the microglial phenotype transition in neurodegenerative diseases. Therefore, the aim of this study was to investigate the role of BACE1 in microglial phagocytosis and inflammatory features in ICH. Here, we demonstrated the unique advantages of targeting BACE1 in microglia using an autologous blood model and primary microglia hemoglobin stimulation. When BACE1 was inhibited early in ICH, fewer residual hematomas remained, consistent with an increase in genetic features that favor phagocytosis and anti-inflammation. In addition, inhibition of BACE1 enhanced the secretion of anti-inflammatory cytokines and substantially reduced the expression of proinflammatory genes, which was regulated by signal transduction and phosphorylation of activator of transcription 3 (STAT3). Further pharmacological inhibition of STAT3 phosphorylation effectively blocked the proinflammatory and weak phagocytic phenotype of microglia due to BACE1 induction. In summary, BACE1 is the critical molecule regulating the inflammatory and phagocytic phenotypes of microglia after ICH, and targeted inhibition of the BACE1/STAT3 pathway is an important strategy for the future treatment of ICH-induced neurological injury.
Abbreviations
ICH: intracerebral hemorrhage; BACE1: β-site amyloid precursor protein (APP) lyase-1; RBCs: red blood cells; STAT3: signal transduction and phosphorylation of activator of transcription 3; CNS: central nervous system; IBA-1: ionized calcium-binding adapter molecule 1; Hb: hemoglobin; PMG: primary microglia; rmBACE1: recombinant mouse BACE1 protein; FACS: Fluorescence-activated cell sorting.