cGAS-STING signaling in Alzheimer's disease: Microglial mechanisms and therapeutic opportunities

IF 10.3 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Aspects of Medicine Pub Date : 2026-02-01 Epub Date: 2026-01-01 DOI:10.1016/j.mam.2025.101444

Faaizah Fazal , Nawab John Dar , Shakir Ahamad , Sameera Khan , Nargis Bano , Supriyo Saha , Aamir Nazir , Shahnawaz Ali Bhat

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引用次数: 0

Abstract

Alzheimer's disease (AD) is increasingly recognized as a neuroinflammatory disorder driven by microglial dysfunction. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway plays a critical role in neuroinflammation and has been strongly implicated in the pathology of AD. Chronic activation of cGAS-STING contributes to neurodegeneration by driving persistent type I interferon release and excessive pro-inflammatory cytokine production. However, the pathway exhibits context-dependent effects. Transient activation promotes antiviral defense, autophagy, and cellular quality control in the central nervous system. Sustained engagement exacerbates neuroinflammation and synaptic loss. Preclinical studies demonstrate that pharmacological inhibitors (such as NR, TSG, H-151, TDI-6750, TDI-8246) mitigate amyloid beta and tau pathology, attenuate microglial reactivity, and enhance cognitive outcomes. Yet, its essential physiological roles, including antimicrobial immunity and autophagy regulation, pose challenges for therapeutic targeting. This potentially disrupts neuroimmune homeostasis. In this review, we highlight the role of cGAS-STING in AD and explore its potential as a therapeutic target using small-molecule drug candidates. Despite these promising findings, challenges remain, including optimizing blood-brain barrier (BBB) penetration, ensuring immune specificity, and addressing long-term safety concerns. Due to these challenges, no cGAS-STING inhibitors have entered clinical trials for AD. However, the future of AD treatment may involve modulation of neuroinflammatory pathways, with cGAS-STING inhibitors playing a central role in reshaping neuroimmune homeostasis.

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cGAS-STING信号在阿尔茨海默病中的作用：小胶质机制和治疗机会

阿尔茨海默病（AD）越来越被认为是一种由小胶质细胞功能障碍驱动的神经炎性疾病。干扰素基因环GMP-AMP合成酶刺激因子（cGAS-STING）通路在神经炎症中起关键作用，并与AD的病理密切相关。cGAS-STING的慢性激活通过驱动持续的I型干扰素释放和过度的促炎细胞因子产生，有助于神经退行性变。然而，该通路表现出环境依赖效应。短暂激活促进中枢神经系统的抗病毒防御、自噬和细胞质量控制。持续接触会加剧神经炎症和突触丧失。临床前研究表明，药物抑制剂（如NR、TSG、H-151、TDI-6750、TDI-8246）可减轻淀粉样蛋白和tau蛋白的病理，减弱小胶质细胞的反应性，并增强认知结果。然而，其重要的生理作用，包括抗微生物免疫和自噬调节，对治疗靶向提出了挑战。这可能会破坏神经免疫稳态。在这篇综述中，我们强调了cGAS-STING在AD中的作用，并探讨了其作为小分子候选药物治疗靶点的潜力。尽管有这些有希望的发现，挑战仍然存在，包括优化血脑屏障（BBB）渗透，确保免疫特异性，以及解决长期安全问题。由于这些挑战，没有cGAS-STING抑制剂进入阿尔茨海默病的临床试验。然而，AD治疗的未来可能涉及神经炎症通路的调节，cGAS-STING抑制剂在重塑神经免疫稳态中发挥核心作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Aspects of Medicine 医学-生化与分子生物学

CiteScore

18.20

自引率

0.00%

发文量

审稿时长

55 days

期刊介绍： Molecular Aspects of Medicine is a review journal that serves as an official publication of the International Union of Biochemistry and Molecular Biology. It caters to physicians and biomedical scientists and aims to bridge the gap between these two fields. The journal encourages practicing clinical scientists to contribute by providing extended reviews on the molecular aspects of a specific medical field. These articles are written in a way that appeals to both doctors who may struggle with basic science and basic scientists who may have limited awareness of clinical practice issues. The journal covers a wide range of medical topics to showcase the molecular insights gained from basic science and highlight the challenging problems that medicine presents to the scientific community.