Understanding the effects of isoDGR in neurodegeneration

Abstract

With the global population aging, the prevalence of chronic diseases such as Alzheimer’s disease and vascular dementia is increasing, emphasizing the urgent need to understand the underlying molecular mechanisms. Degenerative protein modifications (DPMs), including isoAsp-Gly-Arg (isoDGR) motif which is formed via spontaneous deamidation of NGR sequence, are increasingly recognized as contributors to age-related tissue dysfunction. Traditionally considered untreatable molecular damage, isoDGR has been shown to mimic integrin-binding motifs and trigger inflammatory responses, yet its role in neurodegeneration remains poorly understood. In this study, we investigated the effects of isoDGR-motif on key brain cell types, including brain endothelial cells (bEnd3) and neurons (N2A) using in vitro models. IsoDGR exposure induced cellular senescence, characterized by increased β-galactosidase activity, elevated p16 and p53 expression, nuclear translocation of p27, and reduced Lamin B1 levels. We also observed enhanced oxidative stress, particularly mitochondrial ROS, and impaired cell proliferation. Importantly, isoDGR disrupted endothelial monolayer permeability by altering tight junction (ZO-1) and adherens junction (VE-Cadherin) protein expression, increasing permeability and impairing cell migration. ICAM-1 and VCAM-1 expression was also increased in bEnd.3 cells. Together, these findings indicate that isoDGR promotes neuroinflammatory and neurovascular dysfunction, the hallmarks of neurodegenerative disease. This thesis establishes isoDGR as a potential pathophysiological relevant driver of cellular dysfunction in the aging brain. Targeting DPMs such as isoDGR may represent a novel therapeutic approach to mitigate neurodegeneration and extend health-span.