Glial and BBB modifications correlate with early anxio-depressive-like behavior and cognitive inflexibility in 3xTg-AD mice

Multiple studies indicate that alterations in glial cells and the blood-brain barrier (BBB) contribute to anxiety- and depression-like behavior in murine models of depression and chronic stress. Although behavioral and psychological symptoms of dementia (BPSD) represent a major feature of Alzheimer’s disease (AD), this relationship has received limited attention in this pathology. Using the 3xTg-AD mouse model of AD at an early pathological stage (3 months), this study explored the relationship between BPSD and variations of BBB and glial cell markers in specific brain regions (hippocampus dentate gyrus [DG], basolateral amygdala [BLA], infralimbic cortex [IL]). Memory and emotional behaviors were assessed using a battery of behavioral tests. Endothelial tight junction (TJ) proteins, along with astrocyte and microglial markers, were quantified by western blotting and immunohistochemistry in the DG, BLA and IL. While spatial and recognition memory remained intact at this stage, 3xTg-AD mice exhibited an anxio-depressive-like phenotype, impaired coping strategies and reduced cognitive flexibility, with the latter being more pronounced in male than in female. Compared with control mice, 3xTg-AD mice displayed an increased expression of TJ in the DG and BLA, increased microglial cell density in the DG, and fewer and shorter microglial cell branches in the BLA. A principal component analysis revealed a positive correlation between anxio-depressive-like behavior and altered microglial morphology in the BLA, whereas impaired cognitive flexibility positively correlates with ZO-1 expression and microglial cell density in the DG. These findings demonstrate an early association between the BBB, glial cells and AD-related BPSD symptoms in 3-month-old 3xTg-AD mice.