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. |
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| 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 |
| FullText | Links: – Type: other Url: https://resolver.ebsco.com:443/public/rma-ftfapi/ejs/direct?AccessToken=42CEB15FDEDACB6F14E5&Show=Object Text: Availability: 0 CustomLinks: – Url: https://dx.doi.org/doi:10.1007/s12035-026-06081-7 Name: EDS - Springer Nature Journals (s7799221) Category: fullText Text: View record at Springer |
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| Header | DbId: cmedm DbLabel: MEDLINE An: 42554889 AccessLevel: 3 PubType: Academic Journal PubTypeId: academicJournal PreciseRelevancyScore: 0 |
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| Items | – Name: Title Label: Title Group: Ti Data: DNA Sensing Pathways in Innate Immunity: Implications for Alzheimer's Disease Progression and Therapy. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AU" term="%22Shi+C%22">Shi C</searchLink>; 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.<br /><searchLink fieldCode="AU" term="%22Liu+Y%22">Liu Y</searchLink>; Neurology Department, The Medical Center of Chinese, Beijing, China. yli26957@gmail.com.<br /><searchLink fieldCode="AU" term="%22Zhu+Y%22">Zhu Y</searchLink>; Cancer Center, Department of Medical Oncology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China. – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%228900963%22">Molecular neurobiology</searchLink> [Mol Neurobiol] 2026 Aug 05; Vol. 63 (1). <i>Date of Electronic Publication: </i>2026 Aug 05. – Name: TypePub Label: Publication Type Group: TypPub Data: Journal Article; Review – Name: Language Label: Language Group: Lang Data: English – Name: TitleSource Label: Journal Info Group: Src Data: <i>Publisher: </i><searchLink fieldCode="PB" term="%22Humana+Press%22">Humana Press </searchLink><i>Country of Publication: </i>United States <i>NLM ID: </i>8900963 <i>Publication Model: </i>Electronic <i>Cited Medium: </i>Internet <i>ISSN: </i>1559-1182 (Electronic) <i>Linking ISSN: </i><searchLink fieldCode="IS" term="%2208937648%22">08937648 </searchLink><i>NLM ISO Abbreviation: </i>Mol Neurobiol <i>Subsets: </i>MEDLINE – Name: PublisherInfo Label: Imprint Name(s) Group: PubInfo Data: <i>Original Publication</i>: Clifton, NJ : Humana Press, c1987- – Name: SubjectMESH Label: MeSH Terms Group: Su Data: <searchLink fieldCode="MM" term="%22Alzheimer+Disease%22">Alzheimer Disease*</searchLink>/<searchLink fieldCode="MM" term="%22Alzheimer+Disease+immunology%22">immunology</searchLink> <br /><searchLink fieldCode="MM" term="%22Alzheimer+Disease%22">Alzheimer Disease*</searchLink>/<searchLink fieldCode="MM" term="%22Alzheimer+Disease+therapy%22">therapy</searchLink> <br /><searchLink fieldCode="MM" term="%22Alzheimer+Disease%22">Alzheimer Disease*</searchLink>/<searchLink fieldCode="MM" term="%22Alzheimer+Disease+pathology%22">pathology</searchLink> <br /><searchLink fieldCode="MM" term="%22Immunity%2C+Innate%22">Immunity, Innate*</searchLink>/<searchLink fieldCode="MM" term="%22Immunity%2C+Innate+immunology%22">immunology</searchLink> <br /><searchLink fieldCode="MM" term="%22DNA%22">DNA*</searchLink>/<searchLink fieldCode="MM" term="%22DNA+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22DNA%22">DNA*</searchLink>/<searchLink fieldCode="MM" term="%22DNA+immunology%22">immunology</searchLink> <br /><searchLink fieldCode="MM" term="%22Disease+Progression%22">Disease Progression*</searchLink> <br /><searchLink fieldCode="MM" term="%22Signal+Transduction%22">Signal Transduction*</searchLink><br /><searchLink fieldCode="MH" term="%22Toll-Like+Receptor+9%22">Toll-Like Receptor 9</searchLink>/<searchLink fieldCode="MH" term="%22Toll-Like+Receptor+9+metabolism%22">metabolism</searchLink> ; <searchLink fieldCode="MH" term="%22Humans%22">Humans</searchLink> ; <searchLink fieldCode="MH" term="%22Animals%22">Animals</searchLink> ; <searchLink fieldCode="MH" term="%22Innate+Immunity+Recognition%22">Innate Immunity Recognition</searchLink> ; <searchLink fieldCode="MH" term="%22cGAS-STING+Signaling+Pathway%22">cGAS-STING Signaling Pathway</searchLink> ; <searchLink fieldCode="MH" term="%22Cyclic+Guanosine+Monophosphate-Adenosine+Monophosphate+Synthase%22">Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: 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.<br /> (© 2026. The Author(s).) – Name: Abstract Label: Competing Interests Group: Ab Data: 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. – Name: Ref Label: References Group: RefInfo Data: Nat Immunol. 2010 Nov;11(11):997-1004. (PMID: <searchLink fieldCode="PM" term="%2220890285%22">20890285)</searchLink><br />Nat Rev Immunol. 2018 Dec;18(12):759-772. (PMID: <searchLink fieldCode="PM" term="%2230140051%22">30140051)</searchLink><br />Sci Rep. 2017 Jun 15;7(1):3594. 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(PMID: <searchLink fieldCode="PM" term="%2219158679%22">19158679)</searchLink> – Name: SubjectMinor Label: Contributed Indexing Group: Data: <i>Keywords: </i>AIM2 inflammasome; Alzheimer’s disease; CGAS-STING; DNA sensors; Innate immunity; Neuroinflammation; Therapeutic targeting – Name: NumberCAS Label: Substance Nomenclature Group: ID Data: 9007-49-2 (DNA)<br />0 (Toll-Like Receptor 9)<br />EC 2.7.7.86 (Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase) – Name: DateEntry Label: Entry Date(s) Group: Date Data: <i>Date Created: </i>20260805 <i>Date Completed: </i>20260805 <i>Latest Revision: </i>20260813 – Name: DateUpdate Label: Update Code Group: Date Data: 20260814 – Name: PubmedCentralID Label: PubMed Central ID Group: ID Data: PMC13442327 – Name: DOI Label: DOI Group: ID Data: 10.1007/s12035-026-06081-7 – Name: AN Label: PMID Group: ID Data: 42554889 |
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| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1007/s12035-026-06081-7 Languages: – Code: eng Text: English Subjects: – SubjectFull: Toll-Like Receptor 9 metabolism Type: general – SubjectFull: Humans Type: general – SubjectFull: Animals Type: general – SubjectFull: Innate Immunity Recognition Type: general – SubjectFull: cGAS-STING Signaling Pathway Type: general – SubjectFull: Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase Type: general – SubjectFull: Alzheimer Disease immunology Type: general – SubjectFull: Alzheimer Disease therapy Type: general – SubjectFull: Alzheimer Disease pathology Type: general – SubjectFull: Immunity, Innate immunology Type: general – SubjectFull: DNA metabolism Type: general – SubjectFull: DNA immunology Type: general – SubjectFull: Disease Progression Type: general – SubjectFull: Signal Transduction Type: general Titles: – TitleFull: DNA Sensing Pathways in Innate Immunity: Implications for Alzheimer's Disease Progression and Therapy. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Shi C – PersonEntity: Name: NameFull: Liu Y – PersonEntity: Name: NameFull: Zhu Y IsPartOfRelationships: – BibEntity: Dates: – D: 05 M: 08 Text: 2026 Aug 05 Type: published Y: 2026 Identifiers: – Type: issn-electronic Value: 1559-1182 Numbering: – Type: volume Value: 63 – Type: issue Value: 1 Titles: – TitleFull: Molecular neurobiology Type: main |
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