System Maintenance Notice

Please note that maintenance work is scheduled between 4 AM and 5 AM - CET. During this time, you may experience reduced performance. Thanks for your patience.

Publications

Journal Article Epublish

PubMed: 40676669 DOI: 10.1186/s12974-025-03506-3

Modulation of neuronal α1-adrenergic receptor reduces tauopathy and neuroinflammation by inhibiting the STING/NF-κB/NLRP3 signaling pathway in Alzheimer's disease mice.

J Neuroinflammation 22(1):187

Authors: Bo Li, Li Wang, Yan Xiao, Zhi Tang, Yang Wang, Ting Sun, Xiaolan Qi

Affiliations

  • Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education and Key Laboratory of Medical Molecular Biology of Guizhou Province, Key Laboratory of Molecular Biology of Guizhou Medical University, Guiyang, 561113, China.
  • Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education and Key Laboratory of Medical Molecular Biology of Guizhou Province, Key Laboratory of Molecular Biology of Guizhou Medical University, Guiyang, 561113, China. School of Nursing, Guizhou Medical University, Guiyang, 561113, China.
  • The Department of Imaging, Affiliated Hospital of Guizhou Medical University, Guiyang, 550001, China.
  • School of Nursing, Guizhou Medical University, Guiyang, 561113, China.
  • Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education and Key Laboratory of Medical Molecular Biology of Guizhou Province, Key Laboratory of Molecular Biology of Guizhou Medical University, Guiyang, 561113, China. Collaborative Innovation Center for Prevention and Control of Endemic and Ethnic Regional Diseases Constructed By the Province and Ministry, Guiyang, 561113, China.

Abstract

BACKGROUND

Neuroinflammation is closely associated with the pathological progression of Alzheimer's disease (AD). The α1-adrenergic receptor (ADRA1), a G protein-coupled receptor, has been identified as a critical therapeutic target in inflammatory disorders. However, its precise mechanistic role in AD pathogenesis remains unclear.

METHODS

To investigate ADRA1's role in AD, we employed 3xTg-AD and wild-type (WT) mice, modulating neuronal ADRA1 expression via intracerebroventricular delivery of adeno-associated viruses. Cognitive function, tau pathology, neuronal morphology, and activation of the STING/NF-κB/NLRP3 signaling pathway were evaluated using behavioral tests, Western blot, Golgi-Cox staining, immunohistochemistry, and immunofluorescence. In vitro AD models were established using Aβ 42 oligomer-stimulated SH-SY5Y cells and primary murine neurons, along with SH-SY5Y cells transfected with full-length human tau (SH-SY5Y/htau). Pharmacological antagonists, inhibitors, lentiviral transduction, co-immunoprecipitation, and calcium flux assays were utilized to dissect ADRA1-mediated molecular mechanisms in tauopathy and neuroinflammation.

RESULTS

Hippocampal ADRA1 expression was significantly elevated in 10-month-old 3xTg-AD mice. Neuronal ADRA1 knockdown suppressed STING/NF-κB/NLRP3 pathway activation, ameliorated tauopathy and neuroinflammation, restored neuronal structure/function, and improved cognitive deficits in 3xTg-AD mice. Conversely, ADRA1 overexpression in C57/BL6 mice induced tauopathy, neuroinflammation, and cognitive impairment. Mechanistically, ADRA1 interacts with CXCR4 to form heterodimers, triggering cytoplasmic Ca 2⁺ overload and subsequent STING/NF-κB/NLRP3 pathway activation.

CONCLUSIONS

ADRA1 critically mediates tauopathy and neuroinflammation through STING/NF-κB/NLRP3 signaling. These results identify ADRA1 as a promising therapeutic target for AD prevention and treatment.

MeSH

Cells, Adrenergic Agents, Tauopathies, Alzheimer Disease, Receptors, Adrenergic, Cognition Disorders, Therapeutics