Fibrillar tau alters cerebral endothelial cell metabolism, vascular inflammatory activation, and barrier function in vitro and in vivo.

INTRODUCTION: The presence of tau aggregates in and around the brain vasculature in Alzheimer's disease (AD) and tauopathies suggests its possible pathogenicity to cerebral endothelial cells (ECs). METHODS: We used an in vitro model of the blood-brain barrier (BBB) to understand the mechanisms of fibrillar tau-mediated cerebral EC and BBB pathology, confirming our findings in 3-month-old P301S mice brains and extracted microvessels. RESULTS: Protofibrillar and fibrillar tau species induce endothelial barrier permeability through an increase in glycolysis, which activates ECs toward a pro-inflammatory phenotype, inducing loss of junction protein expression and localization. The Warburg-like metabolic shift toward glycolysis and increased vascular pathological phenotypes are also present in young P301S mice. DISCUSSION: In sum, our work reveals that fibrillar tau species, by enhancing endothelial glycolytic metabolism, promote vascular inflammatory phenotypes and loss of BBB function, highlighting the importance of addressing and targeting early tau-mediated neurovascular damage in AD and tauopathies. HIGHLIGHTS: We improve the understanding of the mechanisms of vascular pathology in tauopathies. Fibrillar tau mediates vascular metabolic changes, inflammation, and blood-brain barrier (BBB) dysfunction. These events are replicated at early stages in a tauopathy mouse model. Inhibiting altered glycolysis reduces BBB permeability and endothelial activation.