调节神经元α1-肾上腺素能受体可通过抑制阿尔茨海默病小鼠的STING/NF-κB/NLRP3信号通路来减轻tau蛋白病和神经炎症。

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

作者信息

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

机构信息

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.

出版信息

J Neuroinflammation. 2025 Jul 17;22(1):187. doi: 10.1186/s12974-025-03506-3.

DOI:10.1186/s12974-025-03506-3

PMID:40676669

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 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⁺ 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.

摘要

背景

神经炎症与阿尔茨海默病（AD）的病理进展密切相关。α1 - 肾上腺素能受体（ADRA1）是一种G蛋白偶联受体，已被确定为炎症性疾病的关键治疗靶点。然而，其在AD发病机制中的确切作用机制仍不清楚。

方法

为了研究ADRA1在AD中的作用，我们使用了3xTg - AD小鼠和野生型（WT）小鼠，通过脑室内注射腺相关病毒来调节神经元ADRA1的表达。使用行为测试、蛋白质免疫印迹、高尔基 - 考克斯染色、免疫组织化学和免疫荧光评估认知功能、tau病理、神经元形态以及STING/NF - κB/NLRP3信号通路的激活情况。使用Aβ寡聚体刺激的SH - SY5Y细胞和原代小鼠神经元以及转染了全长人tau蛋白（SH - SY5Y/htau）的SH - SY5Y细胞建立体外AD模型。利用药理学拮抗剂、抑制剂、慢病毒转导、免疫共沉淀和钙流测定来剖析ADRA1介导的tau病变和神经炎症的分子机制。

结果

在10月龄3xTg - AD小鼠中，海马体ADRA1表达显著升高。神经元ADRA1基因敲低抑制了STING/NF - κB/NLRP3通路的激活，改善了tau病变和神经炎症，恢复了神经元结构/功能，并改善了3xTg - AD小鼠的认知缺陷。相反，C57/BL6小鼠中ADRA1过表达诱导了tau病变、神经炎症和认知障碍。机制上，ADRA1与CXCR4相互作用形成异二聚体，引发细胞质Ca⁺过载并随后激活STING/NF - κB/NLRP3通路。