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

Multiple lines of evidence indicate that alterations in glial cells and the blood-brain barrier (BBB) contribute to anxiety- and depression-like behaviors in murine models of depression and chronic stress. Although behavioral and psychological symptoms of dementia (BPSD) represent a major feature of Alzheimers disease (AD), this relationship has received limited attention in this pathology. Using the 3xTg-AD mouse model of AD at an early pathological stage, this study explored the relationship between BPSD and variations of BBB and glial cell markers in specific brain regions (hippocampus, basolateral amygdala [BLA], and prefrontal cortex). 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 or/and immunohistochemistry in the hippocampus, BLA, and prefrontal cortex. While spatial and recognition memory remained intact, 3xTg-AD mice exhibited an anxio-depressive-like phenotype, impaired coping strategies, and reduced cognitive flexibility. Compared with control mice, 3xTg-AD mice displayed an increased expression of TJ proteins in the hippocampus and BLA, increased microglial cell density in the BLA and the dentate gyrus, and fewer and shorter microglial cell branches in the BLA. A principal component analysis revealed a positive correlation between anxio-depressive-like behaviors and altered microglial morphology in the BLA, whereas impaired cognitive flexibility positively correlates with ZO-1 expression and microglial cell density in the hippocampus. These findings demonstrate an early association between the BBB, glial cells and AD-related BPSD symptoms in 3-month-old 3xTg-AD mice.