Activation of Wnt/β‐catenin pathway in the brain endothelium mitigates Aβ‐induced blood‐brain barrier dysfunction in Alzheimer’s disease

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is the leading cause of age‐related neurological and cognitive decline. As the mechanisms of this disease are yet to be fully understood, the treatments for AD pose a significant challenge. Dysfunction 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, underlying mechanisms remain poorly characterized, while few molecules can directly target and improve BBB function in the context of AD.MethodHere using both AD patients and APPswe/PS1dE9 (APP/PS1) mouse model of AD, BBB damage and the underlying molecular mechanism were examined.Resultwe showed dysfunctional BBB in AD patients indicated 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 APP/PS1 mice, BBB dysfunction started at 4 months and became severe at 9 months. In the cerebral microvessels of APP/PS1 mice and Aβ‐treated BECs, we found suppressed Wnt/β‐catenin pathway triggered by an increase of GSK3β activation, but not an inhibition of the AKT pathway or switch 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, Aβ‐inhibited BBB function was restored by promoting the barrier repair and preventing Aβ‐induced BEC impairments.ConclusionTargeting LRP6 in the Wnt/β‐catenin pathway in the brain endothelium can alleviate BBB dysfunction induced by Aβ, which may be a potential treatment strategy for AD.