SOX9 knockdown alleviates Aβ1‑42‑induced neuroinflammation by regulating microglial polarization via inactivation of the ASK1/JNK signaling pathway
Related Experiment Video
Updated: Aug 5, 2026
Direct Gene Knock-out of Axolotl Spinal Cord Neural Stem Cells via Electroporation of CAS9 Protein-gRNA Complexes
Published on: July 9, 2019
Minghui Zheng1, Bingxu Hou2, Ruxue Ma1
1Department of Geriatrics, North China University of Science and Technology Affiliated Hospital, No. 73, Jianshe South Road, Lubei District, Tangshan City, 063000, Hebei Province, China.
Abstract:
Neuroinflammation driven by microglial polarization imbalance plays a key role in Aβ-induced neuronal injury, a core pathological feature of Alzheimer's disease (AD). The transcription factor SOX9 has been linked to AD progression, but its mechanism remains unclear. SOX9 expression was measured in peripheral blood mononuclear cells from 24 patients with AD and 24 age-matched healthy controls and correlated with Montreal Cognitive Assessment scores. An Aβ1-42-stimulated BV-2 cell model was used to investigate the effects of SOX9 and apoptosis signal-regulating kinase 1 (ASK1) on microglial polarization. Neuronal injury was evaluated in a BV-2/SH-SY5Y co-culture system. The transcriptional regulation of ASK1 by SOX9 was examined using dual-luciferase reporter and chromatin immunoprecipitation assays. ASK1 overexpression and the ASK1 inhibitor GS-4997 were used for mechanistic validation. SOX9 expression was increased in peripheral blood mononuclear cells from patients with AD and was negatively correlated with cognitive function. SOX9 was also upregulated in Aβ1-42-stimulated BV-2 cells. SOX9 overexpression enhanced M1-associated inflammatory markers and reduced M2-associated markers, whereas SOX9 knockdown produced the opposite effects. In the co-culture system, SOX9 knockdown increased SH-SY5Y cell viability, reduced LDH release and apoptosis, increased Bcl-2 expression, and decreased Bax and cleaved caspase-3 expression. SOX9 bound to the ASK1 promoter and promoted ASK1 transcription. SOX9 silencing suppressed ASK1, JNK, and p38 phosphorylation, while ASK1 overexpression reversed the effects of SOX9 knockdown on microglial polarization and neuronal injury. Consistently, GS-4997 blocked the pro-inflammatory and neurotoxic effects induced by SOX9 overexpression. SOX9 exacerbates AD neuroinflammation by promoting microglial M1 polarization via the ASK1/JNK signaling axis.
Insights
The transcription factor SOX9 promotes Alzheimer's disease (AD) neuroinflammation by driving microglial M1 polarization through the ASK1/JNK pathway, worsening neuronal injury and cognitive decline.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Neuroinflammation, particularly microglial polarization imbalance, is central to Alzheimer's disease (AD) pathogenesis and Aβ-induced neuronal injury.
- The precise role and mechanism of the transcription factor SOX9 in AD progression remain largely undefined.
Purpose of the Study:
- To elucidate the mechanism by which SOX9 influences neuroinflammation and neuronal injury in Alzheimer's disease.
- To investigate the relationship between SOX9, microglial polarization, and the ASK1/JNK signaling pathway in AD.
Main Methods:
- SOX9 expression analysis in AD patients' PBMCs and correlation with cognitive scores.
- In vitro studies using Aβ1-42-stimulated BV-2 cells and BV-2/SH-SY5Y co-cultures to assess SOX9 effects on microglial polarization and neuronal injury.
- Molecular assays including dual-luciferase reporter and ChIP to determine SOX9 transcriptional regulation of ASK1.
- Pharmacological inhibition of ASK1 and genetic manipulation (overexpression/knockdown) for mechanistic validation.
Main Results:
- SOX9 expression is elevated in AD patients and negatively correlates with cognitive function.
- SOX9 promotes M1 microglial polarization and exacerbates neuronal injury by upregulating ASK1 and activating the ASK1/JNK/p38 signaling axis.
- SOX9 directly binds to the ASK1 promoter, enhancing its transcription, and inhibition of ASK1 or SOX9 mitigates AD-related neuroinflammation and neurotoxicity.
Conclusions:
- SOX9 plays a critical role in exacerbating Alzheimer's disease neuroinflammation.
- The SOX9-mediated promotion of microglial M1 polarization via the ASK1/JNK signaling pathway contributes significantly to AD pathogenesis.
- Targeting SOX9 or the ASK1 pathway presents a potential therapeutic strategy for Alzheimer's disease.