Thanos Jessica M, Campbell Olivia C, Cowan Maureen N, Bruch Katherine R, Moore Katelyn A, Ennerfelt Hannah E, Natale Nick R, Mangalmurti Aman, Kerur Nagaraj, Lukens John R
Department of Neuroscience, Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, Virginia, USA.
Neuroscience Graduate Program, University of Virginia, Charlottesville, Virginia, USA.
Alzheimers Dement. 2025 May;21(5):e70305. doi: 10.1002/alz.70305.
While immune dysfunction has been increasingly linked to Alzheimer's disease (AD) progression, many major innate immune signaling molecules have yet to be explored in AD pathogenesis using genetic targeting approaches.
To investigate a role for the key innate immune adaptor molecule, stimulator of interferon genes (STING), in AD, we deleted Sting1 in the 5xFAD mouse model of AD-related amyloidosis and evaluated the effects on pathology, neuroinflammation, gene expression, and cognition.
Genetic ablation of STING in 5xFAD mice led to improved control of amyloid beta (Aβ) plaques, alterations in microglial activation status, decreased levels of neuritic dystrophy, and protection against cognitive decline. Moreover, rescue of neurological disease in STING-deficient 5xFAD mice was characterized by reduced expression of type I interferon signaling genes in both microglia and excitatory neurons.
These findings reveal critical roles for STING in Aβ-driven neurological disease and suggest that STING-targeting therapeutics may offer promising strategies to treat AD.
Stimulator of interferon genes (STING) deficiency in the 5xFAD mouse model of Alzheimer's disease-related amyloidosis results in decreased amyloid beta (Aβ) deposition and altered microglial activation status. Protection against amyloidosis in STING-deficient 5xFAD mice is associated with decreased expression of genes involved in type I IFN signaling, improved neuronal health, and reduced levels of oxidative stress. Loss of STING in 5xFAD mice leads to improved spatial learning and memory.
虽然免疫功能障碍与阿尔茨海默病（AD）的进展越来越相关，但许多主要的先天性免疫信号分子尚未通过基因靶向方法在AD发病机制中得到探索。
为了研究关键的先天性免疫衔接分子——干扰素基因刺激物（STING）在AD中的作用，我们在与AD相关的淀粉样变性的5xFAD小鼠模型中删除了Sting1，并评估了其对病理、神经炎症、基因表达和认知的影响。
5xFAD小鼠中STING的基因消融导致淀粉样β（Aβ）斑块得到更好的控制，小胶质细胞激活状态改变，神经突营养不良水平降低，并防止认知能力下降。此外，STING缺陷的5xFAD小鼠神经疾病的缓解表现为小胶质细胞和兴奋性神经元中I型干扰素信号基因的表达降低。
这些发现揭示了STING在Aβ驱动的神经疾病中的关键作用，并表明靶向STING的疗法可能为治疗AD提供有前景的策略。
在与阿尔茨海默病相关的淀粉样变性的5xFAD小鼠模型中，干扰素基因刺激物（STING）缺陷导致淀粉样β（Aβ）沉积减少和小胶质细胞激活状态改变。STING缺陷的5xFAD小鼠对淀粉样变性的保护与I型干扰素信号相关基因的表达降低、神经元健康改善和氧化应激水平降低有关。5xFAD小鼠中STING的缺失导致空间学习和记忆改善。
