Activation of Wnt/β-catenin pathway mitigates blood-brain barrier dysfunction in Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder that causes age-dependent neurological and cognitive declines. The treatments for AD pose a significant challenge, because the mechanisms of disease are not being fully understood. Malfunction of the blood-brain barrier (BBB) is increasingly recognized as a major contributor to the pathophysiology of AD, especially at the early stages of the disease. However, the underlying mechanisms remain poorly characterized, while few molecules can directly target and improve BBB function in the context of AD. Here, we showed dysfunctional BBB in AD patients reflected by perivascular accumulation of blood-derived fibrinogen in the hippocampus and cortex, accompanied by decreased tight junction proteins Claudin-5 and glucose transporter Glut-1 in the brain endothelial cells (BECs). In the APPswe/PS1dE9 (APP/PS1) mouse model of AD, BBB dysfunction started at 4 months of age and became severe at 9 months of age. In the cerebral microvessels of APP/PS1 mice and Aβ-treated BECs, we found suppressed Wnt/β-catenin signaling triggered by an increase of GSK3β activation, but not an inhibition of the AKT pathway or switching to the Wnt/planar cell polarity pathway. Furthermore, using our newly developed optogenetic tool for controlled regulation of LRP6 (upstream regulator of the Wnt signaling) to activate Wnt/β-catenin pathway, BBB malfunction was restored by preventing Aβ-induced BEC impairments and promoting the barrier repair. In conclusion, targeting LRP6 in the Wnt/β-catenin pathway in the brain endothelium can alleviate BBB malfunction induced by Aβ, which may be a potential treatment strategy for AD.