DNA damage‐induced neuroinflammation in neurodegenerative disease. (December 2021)

• Record Type: Journal Article
• Authors: Song, Xuan; Ma, Fulin; Herrup, Karl
• Is Part Of: Alzheimer's & dementia. Volume 17(2021)Supplement 3
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-12
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.055175
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Neuroinflammation is a common symptom of many neurodegenerative diseases, including Alzheimer's. It is increasingly appreciated that chronic inflammation, even at low levels, creates a pro‐inflammatory environment that is a major contributor to neuronal cell damage and hence to the symptoms of dementia. We previously showed that DNA damage in microglia leads to DNA fragments "leaking" to the cytoplasm where they trigger a STING‐dependent sterile inflammation. In the present study we ask whether astrocytes are also susceptible to this DNA damage response. Method: Three different types of cultures were used: mixed microglia plus astrocytes, cultures enriched astrocytes, or cultures enriched for microglia. DNA damage was induced either directly by etoposide or indirectly by inhibiting ATM to slow DNA repair. The immune response of the cells was tracked with NFkB immunocytochemistry. Conditioned media (CM) from the treated cultures were collected and applied to established neuronal cultures. Neuronal damage was assessed by measuring morphological changes, synaptic loss and cell death markers along with DNA damage markers. Result: DNA damage led to the accumulation of cytosolic DNA (cytoDNA) in both microglia and astrocytes. In microglia, this specifically activated the STING/AIM2 pathway leading to the overproduction of pro‐inflammatory cytokines, IL‐1β. The involvement of STING in astrocytes is unlikely as its levels are low. Applied to neurons, CM from mixed as well as enriched microglia and astrocyte cultures induced significant neuronal atrophy and death. Unlike microglia, however, low concentrations of astrocyte conditioned media proved to be neurotrophic. Conclusion: Upon DNA damage, microglia and astrocytes both accumulate cytoDNA and, separately or together, they activate a clear neurotoxic response. Our finding that astrocytes and microglia can independently release such neurotoxic substances underscores the complexity of the inflammatory phenotype in aging and Alzheimer's disease and urges a more comprehensive approach to targeting neuroinflammation as a therapeutic strategy.