Sex-Dependent Differences in Amyloid-β Accumulation in a Mouse Model of Alzheimer's Disease

Abstract

Alzheimer’s disease (AD) is a common cause of dementia and has a higher incidence in females. One of the pathological hallmarks of AD is the abnormal accumulation of amyloid-β (Aβ) plaques in the brain, which ultimately results in cognitive decline. It has been hypothesized that the accumulation of Aβ is facilitated by a modified form of Aβ, referred to as pyroglutamate Aβ (Aβ-pE3), which forms the core of Aβ plaques. Additionally, most AD patients display cerebral amyloid angiopathy (CAA), where Aβ accumulates around vessels of the brain. CAA can lead to a reduction in capillary number referred to as capillary rarefaction. This could reduce blood flow to the brain and contribute to the AD-associated cognitive decline. Whether the underlying mechanisms behind the higher incidence of AD in females involve sex differences in Aβ, Aβ-pE3, CAA, or capillary rarefication is not clear. Thus, we used histological techniques to characterize the 5x-FAD mouse model of Aβ accumulation independently of aging to determine if differences in Aβ or Aβ-pE3 accumulation, CAA, and capillary rarefication vary by sex in AD. At 3 months of age, there was no sex difference in Aβ plaque density and coverage in the cortex and hippocampus of 5x-FAD mice. However, female 5x-FAD mice displayed a significantly higher Aβ-pE3 plaque density, coverage, and percentage of Aβ-pE3-cored plaques in those same regions. No sex differences in Aβ and Aβ-pE3 plaque density was observed in 1- and 2-month-old 5x-FAD mice. No differences were observed in blood vessel volume or capillary number when comparing 3-month-old 5xFAD male and female mice to their wild-type littermates. Additionally, CAA was present on the pial vessels and, to a lesser extent, parenchymal vessels of 3-month-old 5x-FAD mice without sex differences. Thus, 3- month-old 5x-FAD mice display sex differences in Aβ-pE3, but not overall Aβ accumulation, CAA, or capillary rarefaction. This sex difference in Aβ-pE3 seemed to not be present in 1- and 2-month-old 5xFAD mice. Although 3-month-old female 5x-FAD mice had an elevated Aβ-pE3 load, no capillary rarefication and parenchymal CAA was observed. This suggests that the microvasculature of these mice is unaffected, at least at the age studied. Future studies are aimed at assessing possible sex differences in the function of these vessels.