CCN1 derived from vascular endothelial cells impairs cognitive function in Alzheimer’s disease model mice

Vascular endothelial cell-expressing molecules regulate neuronal function. Although cerebrovascular dysregulation is a hallmark of Alzheimer's disease (AD), the effect of changes in molecular expression on neuronal function in vascular endothelial cells during disease progression is not clear. In this study, we demonstrated that the cellular communication network factor 1 (CCN1), which is highly expressed in vascular endothelial cells during the chronic stage of AD in mice, is involved in the impairment of cognitive function. Vascular endothelial cells isolated from the brains of App^NL-G-F mice show differential expression of genes, including CCN1. CCN1 treatment decreased the synaptic number in cultured hippocampal cells, with changes in the expression of genes associated with morphological changes. In vivo, App^NL-G-F mice with CCN1 silencing in vascular endothelial cells demonstrated high spine density and improved spatial learning. No significant change was observed in the number of microglia/macrophages, astrocytes, and amyloid-beta (Aβ) accumulation in the hippocampus of the mice. These results suggest that CCN1 is a key factor modulating neurological dysfunction through neurovascular interactions.