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DNA Sensing Pathways in Innate Immunity: Implications for Alzheimer's Disease Progression and Therapy.

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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
Περιγραφή
ISSN:1559-1182
DOI:10.1007/s12035-026-06081-7