Dottorato in NEUROSCIENZE CLINICO-SPERIMENTALI E PSICHIATRIA

Titolo della tesi: “Microglia derived extracellular vesicles (EVs) in brain aging: a rejuvenation approach”

Brain aging presents a picture defined "inflammaging", characterized by high oxidative stress, chronic inflammation and elevated production of inflammatory compounds (López-Otín et al. 2023). Microglia, the immunocompetent cells of the central nervous system, shift towards a chronic low-grade inflammatory state and become hyper-responsive. Indeed, these cells undergo the most prominent aging-related changes in both the morphological and functional phenotypes; their progressive loss of neuroprotective functions affects the whole brain homeostasis. This condition could result in cognitive functions deterioration, lack of motor coordination and memory loss. Microglial phenotype is impacted by aging in a region-dependent manner with hippocampus being more susceptible to age-related modifications during late aging (Grabert et al. 2016). In addition, age-related changes occur differently in aged males and females, since sex hormones are involved in microglial activation and inflammatory response. Extracellular vesicles (EVs) are key players of the inter-cellular communication between donor and recipient cells, through which brain cells exchange packages of molecular information consisting of lipids, proteins and nucleic acids (Budnik et al. 2016). Microglia-derived EVs transport molecular contents that mirror the inflammatory status of donor cells and modulate the inflammatory phenotype of recipient microglia and other cell types. The principal aim of the project was to investigate whether exogenous administration of EVs deriving from microglial-like BV2 cells could be efficient to slow down neuroinflammation in aged mice. To this aim, BV2-derived EVs were analyzed for their molecular, cellular and behavioral effects when administered to 16-20 months-old male and female mice. Data obtained demonstrated that the treatment dampened inflammation, restored a juvenile microglia morphology, reduced anxiety-like behavior while increasing spatial learning, with sex-dependent differences. Results of this thesis has been published in 2024 on the journal “Brain, behavior, and immunity” (Rinaldi & Balietti et al., 2024).