Nicola Mercuri

The vascular endothelial growth factors (VEGFs) and their cognate receptors (VEGFRs), besides their well-known involvement in physiological angiogenesis/lymphangiogenesis and in diseases associated to pathological vessel formation, play multifaceted functions in the central nervous system (CNS). In addition to shaping brain development, by controlling cerebral vasculogenesis and regulating neurogenesis as well as astrocyte differentiation, the VEGFs/VEGFRs axis exerts essential functions in the adult brain both in physiological and pathological contexts. In this article, after describing the physiological VEGFs/VEGFRs functions in the CNS, we focus on the VEGFs/VEGFRs involvement in neurodegenerative diseases by reviewing the current literature on the rather complex VEGFs/VEGFRs contribution to the pathogenic mechanisms of Alzheimer’s (AD) and Parkinson’s (PD) diseases. Thereafter, based on the outcome of VEGFs/VEGFRs targeting in animal models of AD and PD, we discuss the factual relevance of pharmacological VEGFs/VEGFRs modulation as a novel and potential diseasemodifying approach for these neurodegenerative pathologies. Specific VEGFRs targeting, aimed at selective VEGFR-1 inhibition, while preserving VEGFR-2 signal transduction, appears as a promising strategy to hit the molecular mechanisms underlying AD pathology. Moreover, therapeutic VEGFs-based approaches can be proposed for PD treatment, with the aim of fine-tuning their brain levels to amplify neurotrophic/neuroprotective effects while limiting an excessive impact on vascular permeability.

Over the last few decades, emerging evidence suggests that non-coding RNAs (ncRNAs) including long-non-coding RNA (lncRNA), microRNA (miRNA) and circular-RNA (circRNA) contribute to the molecular events underlying progressive neuronal degeneration, and a plethora of ncRNAs have been identified significantly misregulated in many neurodegenerative diseases, including Parkinson’s disease and synucleinopathy. Although a direct link between neuropathology and causative candidates has not been clearly established in many cases, the contribution of ncRNAs to the molecular processes leading to cellular dysfunction observed in neurodegenerative diseases has been addressed, suggesting that they may play a role in the pathophysiology of these diseases. Aim of the present Review is to overview and discuss recent literature focused on the role of RNA-based mechanisms involved in different aspects of neuronal pathology in Parkinson’s disease and synucleinopathy models.