Experimental & Molecular Medicine：阻断STING激活可缓解小胶质细胞功能障碍和广泛的阿尔茨海默病病理-动脉网

Experimental & Molecular Medicine：Blockade of STING activation alleviates microglial dysfunction and a broad spectrum of Alzheimer’s disease pathologies

Nature 等信源发布 2024-09-02 09:05

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AbstractAbnormal glial activation promotes neurodegeneration in Alzheimer’s disease (AD), the most common cause of dementia. Stimulation of the cGAS-STING pathway induces microglial dysfunction and sterile inflammation, which exacerbates AD. We showed that inhibiting STING activation can control microglia and ameliorate a wide spectrum of AD symptoms.

摘要异常的神经胶质激活促进阿尔茨海默病（AD）的神经退行性变，AD是痴呆症的最常见原因。刺激cGAS-STING途径诱导小胶质细胞功能障碍和无菌性炎症，这加剧了AD。我们发现抑制STING激活可以控制小胶质细胞并改善广泛的AD症状。

The cGAS-STING pathway is required for the detection of ectopic DNA and the subsequent immune response. Amyloid-β (Aβ) and tau induce mitochondrial stress, which causes DNA to be released into the cytoplasm of microglia. cGAS and STING are highly expressed in Aβ plaque-associated microglia, and neuronal STING is upregulated in the brains of AD model animals.

cGAS-STING途径是检测异位DNA和随后的免疫应答所必需的。。cGAS和STING在Aβ斑块相关的小胶质细胞中高度表达，并且神经元STING在AD模型动物的大脑中上调。

The presence of the APOE ε4 allele, an AD risk factor, also upregulated both proteins. STING activation was necessary for microglial NLRP3 activation, proinflammatory responses, and type-I-interferon responses. Pharmacological STING inhibition reduced a wide range of AD pathogenic features in AppNL-G-F/hTau double-knock-in mice.

AD危险因素APOEε4等位基因的存在也上调了这两种蛋白质。STING激活对于小胶质细胞NLRP3激活，促炎反应和I型干扰素反应是必需的。药理学STING抑制降低了AppNL-G-F/hTau双敲入小鼠中广泛的AD致病特征。

An unanticipated transcriptome shift in microglia reduced gliosis and cerebral inflammation. Significant reductions in the Aβ load, tau phosphorylation, and microglial synapse engulfment prevented memory loss. To summarize, our study describes the pathogenic mechanism of STING activation as well as its potential as a therapeutic target in AD..

小胶质细胞中意外的转录组转变减少了神经胶质增生和脑部炎症。Aβ负荷，tau磷酸化和小胶质细胞突触吞噬的显着减少阻止了记忆丧失。总之，我们的研究描述了STING激活的致病机制及其作为AD治疗靶点的潜力。。

IntroductionAbnormal immune activation is a consistent feature of neurodegenerative diseases, including Alzheimer’s disease (AD). The accumulation of Aβ and tau triggers an inflammatory response in reactive glial cells, which disrupts normal synaptic function, damages brain tissue, and eventually causes memory loss1.

引言异常免疫激活是包括阿尔茨海默病（AD）在内的神经退行性疾病的一致特征。Aβ和tau的积累引发反应性神经胶质细胞的炎症反应，破坏正常的突触功能，损害脑组织，最终导致记忆丧失1。

Microglia are innate immune cells that are highly sensitive to surrounding microenvironmental stimuli and thus show a wide range of phenotypic alterations in the degenerating brain2. Identifying the causes and key drivers of microglial phenotypic changes is crucial for understanding and modulating the pathophysiology of neurodegenerative diseases3.

小胶质细胞是先天性免疫细胞，对周围的微环境刺激高度敏感，因此在退化的大脑中表现出广泛的表型改变2。确定小胶质细胞表型变化的原因和关键驱动因素对于理解和调节神经退行性疾病的病理生理学至关重要3。

However, due to the wide variety of stimuli present in the diseased brain environment of AD patients, it is challenging to determine which are effective targets for inhibiting microglial dysfunction.Living organisms spontaneously face internal and external challenges to maintain genomic integrity. The relaxation of heterochromatin4, weakening of the nuclear membrane5 and accumulation of DNA damage pose internal risks during aging.

然而，由于AD患者患病大脑环境中存在多种刺激，因此确定哪些是抑制小胶质细胞功能障碍的有效靶标具有挑战性。生物体自发地面临维持基因组完整性的内部和外部挑战。异染色质4的松弛，核膜5的减弱和DNA损伤的积累在衰老过程中构成了内部风险。

Exogenous pathogens also pose risks. Both these intrinsic and extrinsic factors are associated with AD. The accumulation of somatic DNA damage and APP gene recombination have been reported in the brains of AD patients6. Heterochromatin relaxation, which is normally repressed by the polycomb complex, has been reported in sporadic AD neurons7.

外源性病原体也构成风险。。在散发性AD神经元中已经报道了通常被polycomb复合物抑制的异染色质松弛7。

Tau is also known to activate transposable elements8. In the inflammatory environment of the AD brain, Aβ induces DNA damage and mitochondrial stress9. Moreover, other studies have noted the antimicrobial peptide-like properties of Aβ, suggesting that external factors such as viral pathogens can contribute to AD pathogenesis by triggering the body’s.

还已知Tau激活转座因子8。在AD大脑的炎症环境中，Aβ诱导DNA损伤和线粒体应激9。此外，其他研究已经注意到Aβ的抗菌肽样特性，表明诸如病毒病原体之类的外部因素可以通过触发身体来促成AD发病。

TMEM173 knockout iPSC line establishment and iMG differentiationHuman iPSC cell lines were maintained as previously described26. The TMEM173 knockout iPSC line was established by utilizing the CRISPR all-in-one nonviral vector system (abm). On Day 0, the vectors were transfected into the APOE ε4/ε4 iPSC line using LipofectamineTM Stem (Thermo Fisher Scientific).

TMEM173敲除iPSC系的建立和iMG分化如前所述维持人iPSC细胞系26。通过利用CRISPR一体化非病毒载体系统（abm）建立TMEM173敲除iPSC系。在第0天，使用LipofectamineTM Stem（Thermo Fisher Scientific）将载体转染到APOEε4/ε4 iPSC系中。

On Day 3, the culture medium was replaced with Y-27632-supplemented mTeSR1+ to prevent cell death, and GFP-positive cells were sorted and seeded in Matrigel-coated 96-well plates with a SH800S cell sorter (Sony Biotechnology). Grown colonies were sequentially passaged into 24-, 12-, and 6-well plates.

在第3天，将培养基替换为补充有Y-27632的mTeSR1+以防止细胞死亡，并将GFP阳性细胞分选并接种在具有SH800S细胞分选仪（Sony Biotechnology）的Matrigel包被的96孔板中。将生长的菌落依次传代到24孔，12孔和6孔板中。

For confirmation, genomic DNA was extracted, and target sites were PCR amplified and sent for sequencing. Insertions/deletions were confirmed with the Benchling platform (https://www.benchling.com/) and the CRISP-ID v1.1 webtool (http://crispid.gbiomed.kuleuven.be). Potential off-target effects were predicted by the CRISPR RGEN Cas-OFFinder webtool (http://www.rgenome.net/cas-offinder/).

为了确认，提取了基因组DNA，并对靶位点进行了PCR扩增并送去测序。插入/删除已通过Benchling平台确认(https://www.benchling.com/)和CRISP-ID v1.1网络工具(http://crispid.gbiomed.kuleuven.be)。CRISPR RGEN Cas of finder webtool预测了潜在的脱靶效应(http://www.rgenome.net/cas-offinder/)。

iMG differentiation was performed as described in a previous study with some modifications27. The STING-KO iPSC line was obtained from a TMEM173 sgRNA: 5’-AGGTACCGGAGAGTGTGCTC-3’-transfected clone.Immunofluorescence stainingCultured cells were washed with PBS and fixed with 4% paraformaldehyde for 12 min.

如先前的研究中所述进行iMG分化，并进行了一些修改27。STING-KO iPSC系获自TMEM173 sgRNA:5'-AGGTACCGGAGAGTGTGCTC-3'-转染的克隆。免疫荧光染色用PBS洗涤培养的细胞，并用4%多聚甲醛固定12分钟。

The fixed samples were sequentially incubated with 0.3% Triton X-100 for 10 minutes and with blocking solution (2% horse serum, 0.5% BSA) for 20 min at room temperature. Stored brain sections were washed with PBS, treated with 1% Triton X-100 for 10 min and incubated in blocking solution (5% horse serum, 0.5% BSA, 0.3% Triton X-100 in PBS) for 1 h at room temperature.

将固定的样品依次与0.3%Triton X-100孵育10分钟，并在室温下与封闭溶液（2%马血清，0.5%BSA）孵育20分钟。将储存的脑切片用PBS洗涤，用1%Triton X-100处理10分钟，并在封闭溶液（5%马血清，0.5%BSA，0.3%Triton X-100的PBS溶液）中在室温下孵育1小时。

Antigen retrieval was performed by incubation with 70% formic a.

通过与70%甲酸a孵育进行抗原修复。

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Download referencesAcknowledgementsThis research was supported by a grant from the Korea Dementia Research Project through the Korea Dementia Research Center (KDRC), funded by the Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea (grant number: RS-2020-KH106747), the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (grant number: 2020R1A6A3A13070845), and the Korea Basic Science Institute (National research Facilities and Equipment Center) grant funded by the Ministry of Education (grant number: 2021R1A6C101A445).

下载参考文献致谢本研究得到了韩国痴呆症研究项目通过韩国痴呆症研究中心（KDRC）的资助，该中心由韩国卫生福利部和科学与信息通信技术部资助（资助号：RS-2020-KH106747），韩国国家研究基金会（NRF）的基础科学研究计划（资助号：2020R1A6A3A13070845），以及韩国基础科学研究所（国家研究设施和设备中心）的资助（资助号：2021R1A6C101A445）。

The authors thank Dr. T. Saido at RIKEN for providing the AppNL-G-F mice and the MAPT (hTau) knock-in mice. This research partially incorporates the material of Sunwoo Chung’s Ph.D. dissertation at Seoul National University. Graphical summaries were created with BioRender.com.Author informationAuthors and AffiliationsConvergence Dementia Research Center, College of Medicine, Seoul National University, 03080, Seoul, KoreaSunwoo Chung, June-Hyun Jeong, Jong Won Han & Inhee Mook-JungDepartment of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, 03080, Seoul, KoreaSunwoo Chung, June-Hyun Jeong, Jong Won Han, Yeajina Lee, Jong-Il Kim & Inhee Mook-JungDepartment of Biophysics & Institute of Quantum Biophysics, Sungkyunkwan University, 16419, Gyeonggi-do, KoreaJong-Chan ParkGenomic Medicine Institute, Medical Research Center, Seoul National University, 03080, Seoul, KoreaYeajina Lee & Jong-Il KimAuthorsSunwoo ChungView author publicationsYou can also search for this author in.

。这项研究部分结合了Sunwoo Chung在首尔国立大学的博士论文材料。图形摘要是使用BioRender.com.Author informationAuthors and affiliations创建的。首尔国立大学医学院融合痴呆研究中心，03080，首尔，韩国顺武中，June Hyun Jeong，Jong Won Han&Inhee Mook Jung首尔国立大学医学院生物化学与生物医学科学系，03080，首尔，韩国顺武中，June Hyun Jeong，Jong Won Han，Yeajina Lee，Jong Il Kim&Inhee Mook Jung成均馆大学生物物理与量子生物物理研究所，16419，京畿道，韩国顺武大学基因组医学研究所首尔国立大学研究中心，韩国首尔03080李钟郁作者Sunwoo ChungView作者出版物您也可以在中搜索这位作者。

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PubMed Google ScholarContributionsS.C. conducted overall experiments including biochemical, imaging, tissue analysis and behavioral studies, and wrote the manuscript; J.H.J. set up and contributed to behavioral tests and tissue analysis; J.C.P., J.W.H. contributed to human iMG differentiation and experiment.

PubMed谷歌学术贡献。C、进行了全面的实验，包括生化，成像，组织分析和行为研究，并撰写了手稿；J、 H.J.建立并参与行为测试和组织分析；J、 C.P.，J.W.H.为人类iMG分化和实验做出了贡献。

Y.L. and J.K. analyzed transcriptome data. I.M.-J. supervised the overall research, provided intellectual feedback, and wrote the manuscript.Corresponding authorCorrespondence to.

Y、 L.和J.K.分析了转录组数据。一、 M.-J.监督了整个研究，提供了智力反馈，并撰写了手稿。对应作者对应。

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Reprints and permissionsAbout this articleCite this articleChung, S., Jeong, JH., Park, JC. et al. Blockade of STING activation alleviates microglial dysfunction and a broad spectrum of Alzheimer’s disease pathologies.

转载和许可本文引用本文Chung，S.，Jeong，JH。，。阻断STING激活可减轻小胶质细胞功能障碍和广泛的阿尔茨海默病病理。

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