The VEGFs/VEGFRs system in Alzheimer's and Parkinson's diseases: Pathophysiological roles and therapeutic implications

Claudia Ceci; Pedro Miguel Lacal; Maria Luisa Barbaccia; Nicola Biagio Mercuri; Grazia Graziani; Ada Ledonne

doi:10.1016/j.phrs.2024.107101

The VEGFs/VEGFRs system in Alzheimer's and Parkinson's diseases: Pathophysiological roles and therapeutic implications

Pharmacol Res. 2024 Mar:201:107101. doi: 10.1016/j.phrs.2024.107101. Epub 2024 Feb 7.

Authors

Claudia Ceci¹, Pedro Miguel Lacal², Maria Luisa Barbaccia¹, Nicola Biagio Mercuri³, Grazia Graziani⁴, Ada Ledonne⁵

Affiliations

¹ Pharmacology Section, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
² Laboratory of Molecular Oncology, IDI-IRCCS, Rome, Italy.
³ Neurology Section, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; IRCCS Santa Lucia Foundation, Department of Experimental Neuroscience, Rome, Italy; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
⁴ Pharmacology Section, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy. Electronic address: graziani@uniroma2.it.
⁵ Pharmacology Section, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; IRCCS Santa Lucia Foundation, Department of Experimental Neuroscience, Rome, Italy; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.

PMID: 38336311
DOI: 10.1016/j.phrs.2024.107101

Abstract

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 disease-modifying 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.

Keywords: Alzheimer’s disease; Angiogenesis; Axitinib, PubChem CID: 6450551; Cabozantinib, PubChem CID: 25102847; Lenvatinib, PubChem CID: 9823820; Parkinson’s disease; Pazopanib, PubChem CID: 10113978; Ponatinib: PubChem CID 24826799; Regorafenib, PubChem CID: 11167602; Sorafenib, PubChem CID: 216239; Sunitinib, PubChem CID: 5329102; VEGF-A; VEGFR-1; VEGFR-2; Vandetanib, PubChem CID: 3081361.

Publication types

Review

MeSH terms

Alzheimer Disease* / drug therapy
Animals
Brain
Central Nervous System
Parkinson Disease* / drug therapy
Vascular Endothelial Growth Factor Receptor-1

Substances

Vascular Endothelial Growth Factor Receptor-1