Sex differences in a murine model of Cerebral Amyloid Angiopathy

Abstract

Cerebral amyloid angiopathy (CAA) is one of the common causes of lobar intracerebral hemorrhage and vascular cognitive impairment (VCI) in the aging population. Increased amyloid plaque deposition within cerebral blood vessels, specifically the smooth muscle layer, is linked to increased cerebral microbleeds (CMBs) and impaired cognition in CAA. Studies in Alzheimer’s disease (AD) have shown that amyloid plaque pathology is more prevalent in the brains of elderly women (2/3rd of the dementia population) compared with men, however, there is a paucity of studies on sex differences in CAA. The objective of this study was to discern the sexual dichotomies in CAA. We utilized male and female Tg-SwDI mice (mouse model of CAA) at 12–14 months of age for this study. We evaluated sex differences in CMBs, cognitive function and inflammation. Cognition was assessed using Y-maze (spatial working memory) and Fear Conditioning (contextual memory). CMBs were quantified by ex vivo brain MRI scans. Inflammatory cytokines in brain were quantified using ELISA. Our results demonstrated that aging Tg-SwDI female mice had a significantly higher burden of CMBs on MRI as compared to males. Interestingly, these aging Tg-SwDI female mice also had significantly impaired spatial and contextual memory on Y maze and Fear Conditioning respectively. Furthermore, female mice had significantly lower circulating inflammatory cytokines, IL-1α, IL-2, IL-9, and IFN-γ, as compared to males. Our results demonstrate that aging female Tg-SwDI mice are more cognitively impaired and have higher number of CMBs, as compared to males at 12–14 months of age. This may be secondary to reduced levels of neural repair cytokines (IL-1α, IL-2, IL-9 and IFN-γ) involved in sex specific inflammatory signaling in CAA.