VASCO PROJECT

FRRB Project 1739635 - Functional and structural cerebrovascular alterations in neurological disorders: the role of complement

PROJECT SUMMARY

Acute neurological conditions such as ischemic stroke and chronic conditions like Alzheimer's disease have a significant socio-economic impact. According to the latest Global Burden of Disease report from 2019, these two pathologies together account, in Italy, for 8% of DALYs (disability-adjusted life years), representing a measure of the years lived with disability by patients. The decline in cerebral functions observed in both conditions is closely linked to alterations in the cerebral vascular functionality.

The VASCO project aims at elucidating the vascular mechanisms underlying cognitive decline, grounding on the observation that the complement system (CS), a humoral immune response, increases inflammation and brain vascular dysfunction. VASCO endeavors to understand how the CS alters cerebral vascular functionality over time, with the ultimate goal of identifying new therapeutic targets to mitigate cognitive decline associated with acute or chronic neurological conditions. Over the initial two years of the project, novel bi- and three-dimensional cell culture models derived from human induced pluripotent stem cells have been utilized. With these models we studied how vascular damage is associated with a CS protein called mannose-binding lectin (MBL), that contributes to neuronal dysfunction and neuroinflammation. Specifically, the presence of MBL in the vasculature triggers inflammatory events leading to neuronal death and activation of microglia, the principal inflammatory population in the brain. Remarkably, these events are attenuated through MBL inhibition using nanoparticles that expose the natural MBL ligand, mannose. These nanoparticles effectively scavenge MBL, preventing its deposition on blood vessels and thereby limiting its toxic effects.