Potential Protective Role of GNAS in White Matter Lesions in a Chronic Cerebral Hypoperfusion Rat Model

Abstract

Background: Chronic cerebral hypoperfusion (CCH) is recognized as a significant contributor to dementia disease due to the pathological development of white matter lesions (WMLs). This study aimed to investigate cerebral perfusion changes and identify significant differentially expressed genes in the white matter (WM) of a CCH rat model. Methods: CCH was induced in rats through bilateral common carotid artery occlusion (BCCAO) in the BCCAO group while the Sham group underwent blood vessel isolation without ligation. The study involved three cohorts. Cohort 1 (6 rats per group) was longitudinally tracked to assess cerebral perfusion using magnetic resonance imaging arterial spin labeling sequence. Cohort 2 (10 rats per group) underwent cognition assessment via the Morris water maze test and evaluation of myelin damage using Luxol Fast Blue. Cohort 3 rats (6 per group) underwent high-throughput sequencing to identify differentially expressed genes, with expression verified at the gene and protein levels. Furthermore, WM apoptosis was determined via Caspase-3 (CASP3) expression using western blot and double-label immunofluorescence. Results: The CCH group exhibited significantly decreased WM perfusion, cognitive impairment, and myelin disorganization and loss (p < 0.05). High-throughput sequencing identified decreased expression of guanine nucleotide-binding protein, alpha-stimulating activity polypeptide (GNAS) gene which was subsequently validated by real-time polymerase chain reaction (qRT-PCR) and western blot (p < 0.01). Double-label immunofluorescence further corroborated decreased GNAS and increased CASP3 expression in the WM of the BCCAO group compared to the Sham group (p < 0.01). Conclusion: These findings suggest that GNAS may be a protective factor in the WM during CCH. By targeting the GNAS pathway, researchers may be able to develop more effective treatments to delay or inhibit disease progression.