Abstract 105: Sex Differences In The Response To Global Cerebral Hypo-Perfusion In A Mouse Model Of Cerebral Amyloid Angiopathy

Abstract

Cerebral amyloid angiopathy (CAA) is a disease of small and medium-sized vessels, characterized by amyloid deposition. The incidence of CAA increases with age and evidence reveals worsened cognition in females compared to males. Cerebral hypoperfusion, or a decrease in cerebral blood flow (CBF), changes the integrity of the blood brain barrier and contributes to microhemorrhages, cerebral atrophy, and white matter loss. However, the link between vascular amyloid deposition and hypoperfusion remains understudied. We induced global cerebral hypoperfusion with bilateral carotid artery stenosis (BCAS) in CAA mice of both sexes and examined cognitive deficits, white matter loss, and cerebral gliosis. We hypothesize that chronic cerebral hypoperfusion will accelerate cognitive decline in CAA, increase white matter damage, and induce gliotic changes in the brain.Using a mouse model of CAA (Tg-SwDI), male and female mice (3 months of age) were randomized to either BCAS (n=15) or sham (n=11) surgery using 0.18mm coils to induce global cerebral hypoperfusion. Cognitive (Y-maze (YM), NORT, Water Maze (WM)) and motor function (Open Field (OF)) testing was performed by a blinded investigator prior to surgery (baseline) and at regular intervals until tissue harvest 6 months post-BCAS (PB). The brain and brainstem were harvested for immunohistochemical (IHC) analysis (Kluver-Barrera (KB), Iba-1, GFAP, Myelin Basic Protein (MBP)).Sex-specific changes in spatial memory (YM) and learning (NORT/WM) were present in BCAS mice. Female BCAS mice displayed greater deficits in cognition (NORT) at 3 (p=.0028), 4 (YM, p=.0007), and 5-months PB (NORT, p=.0149). Male BCAS mice demonstrated similar cognitive deficits, but at a later timepoint of 5 months PB (NORT, p=.0007). Both female and male BCAS mice had poorer cognition (WM) and motor function (OF, p=.0011/.0055) 6 months PB. IHC demonstrated increased demyelination (MBP) (p=.0038) and atrophy (KB) in the anterior corpus collosum (p=.0447) and significant gliosis (p=.0230).This study shows that chronic global hypoperfusion accelerates cognitive deficits in a CAA model, an effect that is accelerated in female mice. BCAS led to gliotic changes and demyelination associated with white matter damage in the brain.