Role of CGAS-Sting Signaling in Alzheimer's Disease

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2023 May 13

PMID 37175853

Authors

Manoj Govindarajulu

Sindhu Ramesh

McNeil Beasley

Graham Lynn

Caleigh Wallace

Sammie Labeau

Suhrud Pathak

Rishi Nadar

Timothy Moore

Muralikrishnan Dhanasekaran

Affiliations

Soon will be listed here.

Abstract

There is mounting evidence that the development of Alzheimer's disease (AD) interacts extensively with immunological processes in the brain and extends beyond the neuronal compartment. Accumulation of misfolded proteins can activate an innate immune response that releases inflammatory mediators and increases the severity and course of the disease. It is widely known that type-I interferon-driven neuroinflammation in the central nervous system (CNS) accelerates the development of numerous acute and chronic CNS diseases. It is becoming better understood how the cyclic GMP-AMP synthase (cGAS) and its adaptor protein Stimulator of Interferon Genes (STING) triggers type-I IFN-mediated neuroinflammation. We discuss the principal elements of the cGAS-STING signaling pathway and the mechanisms underlying the association between cGAS-STING activity and various AD pathologies. The current understanding of beneficial and harmful cGAS-STING activity in AD and the current treatment pathways being explored will be discussed in this review. The cGAS-STING regulation offers a novel therapeutic opportunity to modulate inflammation in the CNS because it is an upstream regulator of type-I IFNs.

Citing Articles

RhoA/ROCK/GSK3β Signaling: A Keystone in Understanding Alzheimer's Disease.

Medd M, Yon J, Dong H Curr Issues Mol Biol. 2025; 47(2).

PMID: 39996845 PMC: 11854763. DOI: 10.3390/cimb47020124.

Therapeutic Targets in Innate Immunity to Tackle Alzheimer's Disease.

Serradas M, Ding Y, Martorell P, Kulinska I, Castro-Gomez S Cells. 2024; 13(17.

PMID: 39272998 PMC: 11394242. DOI: 10.3390/cells13171426.

mosGraphGPT: a foundation model for multi-omic signaling graphs using generative AI.

Zhang H, Huang D, Chen E, Cao D, Xu T, Dizdar B bioRxiv. 2024; .

PMID: 39149314 PMC: 11326168. DOI: 10.1101/2024.08.01.606222.

Type I interferon signaling, cognition and neurodegeneration following COVID-19: update on a mechanistic pathogenetic model with implications for Alzheimer's disease.

Vavougios G, Tseriotis V, Liampas A, Mavridis T, de Erausquin G, Hadjigeorgiou G Front Hum Neurosci. 2024; 18:1352118.

PMID: 38562226 PMC: 10982434. DOI: 10.3389/fnhum.2024.1352118.

cGAS-STING, an important signaling pathway in diseases and their therapy.

Li Q, Wu P, Du Q, Hanif U, Hu H, Li K MedComm (2020). 2024; 5(4):e511.

PMID: 38525112 PMC: 10960729. DOI: 10.1002/mco2.511.

References

Stetson D, Medzhitov R . Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Immunity. 2006; 24(1):93-103. DOI: 10.1016/j.immuni.2005.12.003. View

Kujirai T, Zierhut C, Takizawa Y, Kim R, Negishi L, Uruma N . Structural basis for the inhibition of cGAS by nucleosomes. Science. 2020; 370(6515):455-458. PMC: 7584773. DOI: 10.1126/science.abd0237. View

Wu Z, Oeck S, Phillip West A, Mangalhara K, Sainz A, Newman L . Mitochondrial DNA Stress Signalling Protects the Nuclear Genome. Nat Metab. 2020; 1(12):1209-1218. PMC: 7213273. DOI: 10.1038/s42255-019-0150-8. View

Kumar V . The Trinity of cGAS, TLR9, and ALRs Guardians of the Cellular Galaxy Against Host-Derived Self-DNA. Front Immunol. 2021; 11:624597. PMC: 7905024. DOI: 10.3389/fimmu.2020.624597. View

Hou Y, Wei Y, Lautrup S, Yang B, Wang Y, Cordonnier S . NAD supplementation reduces neuroinflammation and cell senescence in a transgenic mouse model of Alzheimer's disease via cGAS-STING. Proc Natl Acad Sci U S A. 2021; 118(37). PMC: 8449423. DOI: 10.1073/pnas.2011226118. View

Guo C, Jeong H, Hsieh Y, Klein H, Bennett D, De Jager P . Tau Activates Transposable Elements in Alzheimer's Disease. Cell Rep. 2018; 23(10):2874-2880. PMC: 6181645. DOI: 10.1016/j.celrep.2018.05.004. View

Taylor J, Moore Z, Minter M, Crack P . Type-I interferon pathway in neuroinflammation and neurodegeneration: focus on Alzheimer's disease. J Neural Transm (Vienna). 2017; 125(5):797-807. DOI: 10.1007/s00702-017-1745-4. View

Cai Q, Jeong Y . Mitophagy in Alzheimer's Disease and Other Age-Related Neurodegenerative Diseases. Cells. 2020; 9(1). PMC: 7017092. DOI: 10.3390/cells9010150. View

Luo W, Wang Y, Zhang L, Ren P, Zhang C, Li Y . Critical Role of Cytosolic DNA and Its Sensing Adaptor STING in Aortic Degeneration, Dissection, and Rupture. Circulation. 2019; 141(1):42-66. PMC: 6939474. DOI: 10.1161/CIRCULATIONAHA.119.041460. View

10.

Sheridan C . Drug developers switch gears to inhibit STING. Nat Biotechnol. 2019; 37(3):199-201. DOI: 10.1038/s41587-019-0060-z. View

11.

Phillip West A, Khoury-Hanold W, Staron M, Tal M, Pineda C, Lang S . Mitochondrial DNA stress primes the antiviral innate immune response. Nature. 2015; 520(7548):553-7. PMC: 4409480. DOI: 10.1038/nature14156. View

12.

Moya G, Rivera P, Dittenhafer-Reed K . Evidence for the Role of Mitochondrial DNA Release in the Inflammatory Response in Neurological Disorders. Int J Mol Sci. 2021; 22(13). PMC: 8268735. DOI: 10.3390/ijms22137030. View

13.

Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland T . A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease. Cell. 2017; 169(7):1276-1290.e17. DOI: 10.1016/j.cell.2017.05.018. View

14.

Barrett J, Henry R, Shirey K, Doran S, Makarevich O, Ritzel R . Interferon-β Plays a Detrimental Role in Experimental Traumatic Brain Injury by Enhancing Neuroinflammation That Drives Chronic Neurodegeneration. J Neurosci. 2020; 40(11):2357-2370. PMC: 7083281. DOI: 10.1523/JNEUROSCI.2516-19.2020. View

15.

Takahashi K, Rochford C, Neumann H . Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J Exp Med. 2005; 201(4):647-57. PMC: 2213053. DOI: 10.1084/jem.20041611. View

16.

Yang H, Wang H, Ren J, Chen Q, Chen Z . cGAS is essential for cellular senescence. Proc Natl Acad Sci U S A. 2017; 114(23):E4612-E4620. PMC: 5468617. DOI: 10.1073/pnas.1705499114. View

17.

Sliter D, Martinez J, Hao L, Chen X, Sun N, Fischer T . Parkin and PINK1 mitigate STING-induced inflammation. Nature. 2018; 561(7722):258-262. PMC: 7362342. DOI: 10.1038/s41586-018-0448-9. View

18.

Jiang T, Yu J, Zhu X, Tan M, Gu L, Zhang Y . Triggering receptor expressed on myeloid cells 2 knockdown exacerbates aging-related neuroinflammation and cognitive deficiency in senescence-accelerated mouse prone 8 mice. Neurobiol Aging. 2013; 35(6):1243-51. DOI: 10.1016/j.neurobiolaging.2013.11.026. View

19.

Murthy A, Robinson N, Kumar S . Crosstalk between cGAS-STING signaling and cell death. Cell Death Differ. 2020; 27(11):2989-3003. PMC: 7560597. DOI: 10.1038/s41418-020-00624-8. View

20.

Xie X, Ma G, Li X, Zhao J, Zhao Z, Zeng J . Activation of innate immune cGAS-STING pathway contributes to Alzheimer's pathogenesis in 5×FAD mice. Nat Aging. 2023; 3(2):202-212. DOI: 10.1038/s43587-022-00337-2. View