Extracellular Vesicle treatment and age-related neuropathology in non-human primates

Boston University Medical Campus, Boston MA

Investigators

Abstract

ABSTRACT In our previous grant (R01AG068168) we demonstrated the efficacy of mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) from young monkeys to slow or reverse age-related cognitive decline in aging rhesus monkeys. Compared to controls, EV-treated monkeys showed a higher level of performance on a spatial working memory task, which was correlated with increased Aβ42 protein concentration in the CSF, possibly due to enhanced clearance. EV-mediated improved spatial working memory was also correlated with enhanced white matter integrity, functional connectivity in vivo and greater excitability of pyramidal neurons in prefrontal cortex, pointing to compensatory mechanisms that may promote plasticity during aging. In addition, extensive proteomic profiling of the contents of our monkey EVs identified the enrichment of proteins involved in several neuritogenic and synaptogenic processes that provide mechanistic insight on the ability of the EVs to ameliorate age-related changes in the brain. Furthermore, our in vitro studies showed that EVs mitigate age- and AD-related neurodegenerative changes in human-derived cortical organoids (COs). Together these findings demonstrate the significant therapeutic efficacy of MSC-EVs in aging. However, recent evidence has demonstrated sex differences in the cargo and gene expression in EVs. Recent transcriptomic studies have demonstrated that EVs from male donors express a greater variety and abundance of RNAs than those from female donors.6 Further, differentially expressed genes (DEG) in male EVs were associated with intracellular signaling and vesicle transport, whereas DEGs in female EVs were associated with extracellular matrix organization and signal transmission. These outcomes suggest that male and female EVs may support different biological, repair and immunomodulatory processes and therefore may have different effects on the aged brain.6 In the previous grant, our studies used EVs from both male and female donors. However, our most recent data showed a positive effect of female EVs on cognition, white matter integrity and neuropathological debris clearance. In this renewal, we now propose to conduct an in-depth analysis of the mechanistic action and efficacy of EVs from MSCs from both male and female donors, to determine sex differences in the ability of EVs to ameliorate age-related impairments in cognition, facilitate clearance of neurodegenerative debris and reduce inflammation in monkeys and human-derived COs. Based on our data and evidence from the literature we hypothesize that EVs derived from female MSCs will have more efficacious therapeutic benefits, including increased clearance of age-related neurodegenerative debris that will correlate with white matter integrity, neuronal plasticity and improved cognitive function.