APOE genotype and sex affect astrocyte interactions with amyloid plaques in EFAD transgenic mice.

Abstract

Glial interactions with plaques are thought to affect Alzheimer's disease (AD) pathogenesis in both beneficial and deleterious manners. Positive effects of microglial interactions with amyloid plaques include both plaque compaction and protection of local neurites, perhaps resulting from barrier-like microglial formations. We previously demonstrated that both APOE4 genotype and female sex are associated with impaired microglial interactions with plaques. Although it is well-established that astrocytes have bidirectional functional interactions with microglia and are localized in close proximity to amyloid plaques, the role of astrocyte-plaque interactions are not well understood. Further, the potential moderating effects of APOE genotype and biological sex have not been investigated with regards to astrocyte-plaque interactions in AD. To investigate the role of APOE genotype and biological sex on astrocyte interactions with Aβ plaques, we studied both male and female EFAD mice, which have mouse APOE replaced with human APOE and are hemizygous for the 5xFAD transgenes. Fixed brains from 6-month-old mice were stained with amyloid dyes, immunolabeled with markers of astrocytes, microglia, and dystrophic neurites and analyzed with quantitative, high-resolution confocal microscopy. We observed that astrocytic processes interact with plaques in a similar way to microglia, in which coverage was highest in male APOE3 mice. Importantly, significant reductions in astrocyte coverage of amyloid plaques was observed with both APOE4 genotype and female sex. Plaque compaction also showed a similar pattern where APOE4 genotype and female sex were associated with significantly lower values relative to male sex and APOE3 genotype. Functionally, neuritic dystrophy was significantly higher with both APOE4 genotype and female sex within the plaque environment. These findings suggest that astrocytes complement microglial plaque coverage in a manner that appears to protect the neuronal milieu from plaque-associated damage. These protective astrocytic interactions are dependent on APOE genotype and sex, with outcomes being best in males with APOE3 and poorest in females with APOE4. Collectively, these findings provide new insight into the role of glia as contributors to the relationships among sex, APOE, and AD.