Boosting NAD in senescent microglia to fight neurodegeneration?

In neurodegenerative disorders and senescence, microglia, the brain immune cells, acquire a disease-associated microglia signature that may favor tissue repair in early disease state but at late stages lose its protective homeostatic functions. Senescent microglia exhibit a secretory associated senescence phenotype, deficits in phagocytosis, and impaired metabolism, with depletion of NAD, which plays a central role in genome integrity and cell metabolism. Emerging evidence highlighted lower levels of NAD in senescence and neurodegenerative diseases, with consequent impairment of sirtuins’ activity. The aim of this study was to investigate changes that occur during senescence in microglia developing an in vitro model of chronically exposure (up to 30 days) to high iron concentration. Initially, iron treatment induces microglia to proliferate more, enhances phagocytosis, and increase NAD levels suggesting microglia activation. After 30 days of treatment microglia acquired a senescent-like phenotype characterized by proliferation arrest, decreased phagocytosis, upregulation of SASP markers with a significant increase in EVs production. Biochemical analyses showed decreased levels in NAD content in iron-treated microglia, concomitantly to an increased expression of CD38 (the major NAD consuming enzyme). Moreover, the levels and activity of Sirtuin 6, which is downregulated in aged/senescent cells, were strongly reduced compared to control microglia. Senescent microglia co-cultured with healthy microglia induced senescent traits in healthy cells, as revealed by a significant increase in SA-ß-Gal and p21 positive cells and in reduced levels of NAD. We are currently trying to understand the molecular mechanism underlying senescence propagation to healthy cells.