Cerebral Vascular Alterations in a Mouse Model of Alzheimer's Disease Are Dependent on Biological Sex

Abstract

Alzheimer's disease (AD)- associated dementia, one of the most common forms of cognitive decline, shows a higher incidence in women than men. One of the underlying factors for dementia is improper regulation of cerebral blood flow, which can be a consequence of brain vascular dysfunction caused by perivascular amyloid-β deposition, a peptide linked to the AD pathology. However, it is unknown if there are sex differences in cerebral vascular function and structure in AD that account for the sex differences with respect to AD-associated dementia. We hypothesized that AD induces a more pronounced cerebral vascular dysfunction and remodeling in females in a mouse model of AD with pial artery amyloid-β accumulation, the 5x-FAD. Posterior communicating arteries (PComA) from 5x-FAD and wild-type (WT) mice were isolated and cannulated in a pressure myograph to analyze: spontaneous myogenic tone, autoregulation, vasoconstrictor response to endothelin-1 (ET-1, 30 nM) and passive vascular parameters. Data are means ± SEM. In males, spontaneous myogenic tone was significantly higher in 5x-FAD than WT (tone (%): 20.8 ± 2.4 vs 14.2 ± 1.0, 5x-FAD vs WT, n = 8-7, p<0.05, Student's t-test), without changes in autoregulation and constriction to ET-1 between strains. PComA from 5x-FAD males showed inward remodeling, observed as a reduction in lumen diameter across the range of intraluminal pressures (at 60 mmHg: 71.5 ± 8.0 µm vs 87.3± 8.1 µm, 5x-FAD vs WT, n = 6-11, p<0.05, two-way ANOVA), without alterations in wall thickness. Distensibility was lower in male 5x-FAD at higher pressures (% diameter increase from 5 mmHg to 120 mmHg: 63.8 ± 5.9 vs 46.9 ± 5.8, 5x-FAD vs WT, p <0.05, two-way ANOVA) without changes in stiffness. In females, spontaneous myogenic tone (tone (%): 20.1 ± 1.8 vs 25.5 ± 3.7, 5x-FAD vs WT, n = 16-8, p> 0.05), autoregulation and constriction to ET-1 were not different between strains. Similarly, no structural remodeling was observed in the PComA of 5x-FAD females, except for a small but significant increase in distensibility at lower pressures (at 20 mmHg: 20.2 ± 3.2 vs 16.9 ± 3.0, 5x-FAD vs WT p<0.05), without changes in stiffness. We conclude that, contrary to the hypothesis, PComA from female 5x-FAD do not exhibit dysfunction or remodeling at 3-4 months of age, despite amyloid-β deposition being evident. However, PComA from 5x-FAD male show increased spontaneous myogenic tone, inward remodeling and a small reduction in distensibility. These results reveal that premenopausal women may be protected from AD-associated vascular dysfunction. Further, the increase in incidence of dementia in females may occur by pathophysiological changes occurring during menopause.