Academic Journal
DNA Sensing Pathways in Innate Immunity: Implications for Alzheimer's Disease Progression and Therapy.
| Τίτλος: | DNA Sensing Pathways in Innate Immunity: Implications for Alzheimer's Disease Progression and Therapy. |
|---|---|
| Συγγραφείς: | Shi C; Center for Rehabilitation Medicine, Department of Rehabilitation Medicine, Rehabilitation & Sports Medicine Research Institute of Zhejiang Province, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China., Liu Y; Neurology Department, The Medical Center of Chinese, Beijing, China. yli26957@gmail.com., Zhu Y; Cancer Center, Department of Medical Oncology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China. |
| Πηγή: | Molecular neurobiology [Mol Neurobiol] 2026 Aug 05; Vol. 63 (1). Date of Electronic Publication: 2026 Aug 05. |
| Τύπος έκδοσης: | Journal Article; Review |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Humana Press Country of Publication: United States NLM ID: 8900963 Publication Model: Electronic Cited Medium: Internet ISSN: 1559-1182 (Electronic) Linking ISSN: 08937648 NLM ISO Abbreviation: Mol Neurobiol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Clifton, NJ : Humana Press, c1987- |
| Ιατρικοί όροι (MeSH): | Alzheimer Disease*/immunology , Alzheimer Disease*/therapy , Alzheimer Disease*/pathology , Immunity, Innate*/immunology , DNA*/metabolism , DNA*/immunology , Disease Progression* , Signal Transduction*, Toll-Like Receptor 9/metabolism ; Humans ; Animals ; Innate Immunity Recognition ; cGAS-STING Signaling Pathway ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase |
| Περίληψη: | DNA sensors are emerging regulators of innate immune activation in Alzheimer's disease (AD). In addition to detecting microbial DNA, these pattern-recognition receptors can respond to cytosolic or endosomal self-DNA generated by DNA damage, mitochondrial dysfunction, impaired DNA repair, cellular stress, or neuronal injury. Aberrant activation of DNA-sensing pathways may amplify neuroinflammation through type I interferon (IFN-I) signaling, inflammasome activation, pyroptosis, and microglial dysfunction, thereby contributing to amyloid pathology, tau-related inflammation, synaptic loss, and cognitive decline. In this review, we summarize current evidence linking major DNA sensors, including cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING), absent in melanoma 2 (AIM2), toll-like receptor 9 (TLR9) to AD pathogenesis. We emphasize the strongest available evidence for cGAS-STING and AIM2, discuss the context-dependent roles of TLR9, and highlight less-established sensors requiring further validation. Finally, we evaluate therapeutic strategies targeting DNA-sensing pathways, including pathway inhibition and controlled immune activation, and discuss translational challenges such as blood-brain barrier penetration, off-target effects, dose dependency, and disease-stage-specific modulation. (© 2026. The Author(s).) |
| Competing Interests: | Declarations. Ethical Approval and Consent to Participate: It is not applicable. Consent for Publication: It is not applicable. Competing interests: The authors declare no competing interests. Clinical Trial Number: Not applicable. |
| References: | Nat Immunol. 2010 Nov;11(11):997-1004. (PMID: 20890285) Nat Rev Immunol. 2018 Dec;18(12):759-772. (PMID: 30140051) Sci Rep. 2017 Jun 15;7(1):3594. (PMID: 28620207) Cell Death Differ. 2008 Nov;15(11):1760-71. (PMID: 18636074) Proc Natl Acad Sci U S A. 2021 Sep 14;118(37):. (PMID: 34497121) Nat Immunol. 2015 Mar;16(3):229-36. (PMID: 25689443) J Med Virol. 2017 Dec;89(12):2188-2195. (PMID: 28480966) J Neural Transm (Vienna). 2018 May;125(5):797-807. (PMID: 28676934) Nat Neurosci. 2023 May;26(5):737-750. (PMID: 37095396) Microbiol Immunol. 2019 Feb;63(2):51-64. (PMID: 30677166) Cell. 2026 Jan 22;189(2):640-658.e22. (PMID: 41270732) Acta Neuropathol Commun. 2014 Sep 02;2:101. (PMID: 25178404) Mutat Res. 2015 Jun;776:84-97. (PMID: 26255941) Lancet Neurol. 2019 Jan;18(1):88-106. (PMID: 30497964) Eur J Pharmacol. 2023 Aug 15;953:175809. (PMID: 37328043) Neuron. 2018 Mar 7;97(5):1023-1031.e7. (PMID: 29518356) Mol Neurobiol. 2021 Jan;58(1):118-131. (PMID: 32895786) Nature. 2009 Mar 26;458(7237):509-13. (PMID: 19158676) Sci Rep. 2017 Dec 1;7(1):16760. (PMID: 29196629) Nat Aging. 2023 Feb;3(2):202-212. (PMID: 37118112) Nature. 2019 Nov;575(7784):669-673. (PMID: 31748742) Science. 2010 Jan 15;327(5963):291-5. (PMID: 20075244) Curr Neuropharmacol. 2019;17(12):1146-1157. (PMID: 31362659) Nature. 2008 Dec 4;456(7222):658-62. (PMID: 18820679) Nat Neurosci. 2017 Oct;20(10):1371-1376. (PMID: 28846081) Mol Cell. 2019 May 16;74(4):801-815.e6. (PMID: 30952515) Acta Neuropathol. 2019 Apr;137(4):599-617. (PMID: 30721409) Free Radic Biol Med. 2024 Nov 1;224:204-219. (PMID: 39197597) Immunity. 2025 Oct 14;58(10):2574-2592.e9. (PMID: 40902587) PLoS Pathog. 2019 Dec 26;15(12):e1008239. (PMID: 31877196) Nature. 2007 Jul 26;448(7152):501-5. (PMID: 17618271) Genes Dev. 2017 Feb 15;31(4):353-369. (PMID: 28279982) J Neurochem. 2005 Jul;94(2):289-98. (PMID: 15998280) Cell Res. 2007 Oct;17(10):834-5. (PMID: 17934493) Neuroscience. 2025 Apr 19;572:122-133. (PMID: 40064364) Front Pharmacol. 2019 Apr 16;10:395. (PMID: 31040784) J Neurosci. 2009 Feb 11;29(6):1846-54. (PMID: 19211891) Nature. 2017 Aug 24;548(7668):461-465. (PMID: 28738408) Front Immunol. 2018 Jun 14;9:1297. (PMID: 29963044) Nat Immunol. 2011 Sep 04;12(10):959-65. (PMID: 21892174) Mol Psychiatry. 2023 Dec;28(12):5380-5389. (PMID: 37433968) Front Immunol. 2018 Apr 09;9:586. (PMID: 29686666) Exp Mol Med. 2024 Sep;56(9):1936-1951. (PMID: 39218977) J Neuroinflammation. 2021 Dec 3;18(1):281. (PMID: 34861878) Glia. 2015 May;63(5):812-25. (PMID: 25627810) Mutagenesis. 2011 Jan;26(1):85-92. (PMID: 21164187) Neuroimmunomodulation. 2017;24(1):29-39. (PMID: 28618410) Nat Commun. 2020 May 18;11(1):2484. (PMID: 32424276) J Alzheimers Dis. 2025 Mar;104(1):150-157. (PMID: 39962970) Nat Immunol. 2006 Feb;7(2):156-64. (PMID: 16415873) J Neuroinflammation. 2013 Aug 20;10:101. (PMID: 23957925) Science. 2019 Mar 8;363(6431):. (PMID: 30846571) J Neuroinflammation. 2018 Sep 18;15(1):269. (PMID: 30227881) Nat Commun. 2021 Nov 15;12(1):6565. (PMID: 34782623) Nature. 2020 Oct;586(7831):735-740. (PMID: 32879487) Food Funct. 2025 Oct 27;16(21):8320-8344. (PMID: 41085348) Nature. 2015 Oct 29;526(7575):666-71. (PMID: 26375259) J Neurosci. 2017 Jan 25;37(4):936-959. (PMID: 28123027) J Immunol. 2016 Jan 1;196(1):29-33. (PMID: 26590313) J Neuroinflammation. 2021 Dec 2;18(1):280. (PMID: 34856990) J Leukoc Biol. 2009 Dec;86(6):1359-63. (PMID: 19759281) Cell. 2019 Oct 3;179(2):312-339. (PMID: 31564456) Brain Behav Immun. 2019 Oct;81:495-508. (PMID: 31283973) Acta Neuropathol Commun. 2019 May 17;7(1):77. (PMID: 31101070) Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):9237-42. (PMID: 11470918) Brain. 2021 Aug 17;144(7):2146-2165. (PMID: 34128045) Mutagenesis. 2011 Jan;26(1):125-32. (PMID: 21164193) CNS Neurosci Ther. 2024 Jun;30(6):e14555. (PMID: 38105588) J Clin Invest. 2020 Apr 1;130(4):1912-1930. (PMID: 31917687) PLoS One. 2011;6(5):e19125. (PMID: 21625537) Crit Rev Food Sci Nutr. 2026;66(12):2335-2351. (PMID: 41044993) Nat Rev Genet. 2013 Mar;14(3):204-20. (PMID: 23400093) Biophys Rev. 2016 Mar;8(1):33-43. (PMID: 28510149) Mol Cell. 2018 Sep 6;71(5):745-760.e5. (PMID: 30193098) Mol Cell. 2013 Jul 25;51(2):226-35. (PMID: 23747010) Ann N Y Acad Sci. 2009 Feb;1153:240-6. (PMID: 19236346) Immunol Rev. 2011 Sep;243(1):206-14. (PMID: 21884178) Brain Res Bull. 2019 Oct;152:85-94. (PMID: 31301379) Bioessays. 2025 Mar;47(3):e202400111. (PMID: 39821800) J Cereb Blood Flow Metab. 2014 Apr;34(4):621-9. (PMID: 24398937) Int J Mol Sci. 2020 Feb 28;21(5):. (PMID: 32121304) J Clin Invest. 2018 Apr 2;128(4):1238-1246. (PMID: 29608137) Biomed Res Int. 2019 Jan 21;2019:9642589. (PMID: 30809552) Nat Immunol. 2012 Dec;13(12):1155-61. (PMID: 23142775) Nat Immunol. 2009 Mar;10(3):266-72. (PMID: 19158679) |
| Contributed Indexing: | Keywords: AIM2 inflammasome; Alzheimer’s disease; CGAS-STING; DNA sensors; Innate immunity; Neuroinflammation; Therapeutic targeting |
| Substance Nomenclature: | 9007-49-2 (DNA) 0 (Toll-Like Receptor 9) EC 2.7.7.86 (Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase) |
| Entry Date(s): | Date Created: 20260805 Date Completed: 20260805 Latest Revision: 20260813 |
| Update Code: | 20260814 |
| PubMed Central ID: | PMC13442327 |
| DOI: | 10.1007/s12035-026-06081-7 |
| PMID: | 42554889 |
| Βάση Δεδομένων: | MEDLINE |
καταχωρήστε σχόλιο πρώτοι!