Hippocampal α1-adrenergic receptor (ADRA1) expression was significantly elevated in 10-month-old 3xTg-AD mice.
Neuronal knockdown of ADRA1 suppressed the activation of the STING/NF-κB/NLRP3 signaling pathway.
This knockdown ameliorated and , restored neuronal structure and function, and improved cognitive deficits.
Conversely, overexpression of ADRA1 in C57/BL6 mice led to increased tauopathy, neuroinflammation, and cognitive impairment.
ADRA1 may interact with CXCR4 to form heterodimers, which could trigger cytoplasmic calcium overload and activate the STING/NF-κB/NLRP3 pathway.
ADRA1 is associated with critical processes in tauopathy and neuroinflammation, suggesting its potential as a therapeutic target for Alzheimer's disease.
Simplified
BACKGROUND: 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 Aβoligomer-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 and neuroinflammation. 42
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⁺ overload and subsequent STING/NF-κB/NLRP3 pathway activation. 2
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.
Key numbers
10 months
Increase in ADRA1 Expression
Elevated ADRA1 levels observed in 10-month-old 3xTg-AD mice.
4 weeks
Improvement in Cognitive Function
Cognitive assessments conducted 4 weeks post ADRA1 knockdown in 3xTg-AD mice.
6
Reduction
Western blot analysis of STING and NF-κB components across experimental groups.
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Declarations. Ethics approval and consent to participate: All animal experiments received approval from the Institutional Animal Care and Use Committee of Guizhou Medical University (approval No.2402660). The experiments were conducted in accordance with ARRIVE 2.0 guidelines, as approved by the Animal Protection and Use Committee of Guizhou Medical University. Consent for publication: All the authors agree with the submission of this manuscript. Competing interests: The authors declare no competing interests.
