Retinal vascular dysfunction in the Mthfr677C>T mouse model of cerebrovascular disease

Abstract INTRODUCTION Investigations of retinal biomarkers for Alzheimer's disease (AD) and AD and related dementias (ADRD), has increased significantly. We examine retinal vascular health in a mouse containing the ADRD risk variant Mthfr 677C>T to determine if changes in retina mirror similar changes in cerebrovasculature. METHODS Morphology and function of retinal vasculature and neurons were assessed using in vivo imaging, immunohistochemistry, and pattern electroretinography. RNAscope and proteomics were employed to determine Mthfr gene expression and differential protein expression in mice carrying Mthfr 677C>T . RESULTS Mice show age‐ and sex‐dependent retinal vascular deficits, displaying similarities to previously published brain data. Mthfr is widely expressed and co‐localizes with vascular cell markers. Proteomics identified common molecular signatures across the brain and retina. DISCUSSION Results demonstrate that Mthfr ‐dependent vascular phenotypes occur in brain and retina similarly. These data suggest that assessing age and genetic‐driven changes within retinal vasculature represents a minimally invasive method to predict AD‐related cerebrovascular damage. Highlights Mthfr 677C>T retinal vascular phenotypes align with cerebrovascular phenotypes. Mthfr 677C>T brain and retina share Alzheimer's disease (AD)–)relevant differentially expressed proteins. Retinal imaging may provide insight regarding genetic risk for vascular dysfunction.