Endothelial adenosine A2A receptor activation-mediated Tau hyperphosphorylation leads to blood-brain barrier breakdown in a chronic methamphetamine mouse model.

INTRODUCTION: Methamphetamine (METH), a psychostimulant, can cause the blood-brain barrier (BBB) breakdown through astrocyte endfeet swelling and endothelial cell impairment. Our previous studies have shown that phosphorylated microtubule-associated protein Tau (p-Tau) levels increase, especially in neurons, after METH exposure. However, whether p-Tau accumulates in the endothelial cells of METH mouse brains remains unclear. The effects of endothelial p-Tau accumulation on BBB integrity in a chronic METH mouse model are elusive.

METHODS: The A2AR-GSK3β signaling pathway protein levels were evaluated in chronic METH mice model. The BBB integrity, endothelial p-Tau level and behavioral performances were tested after A2AR inhibiton, GSK3β inhibition or p-Tau knockout.

RESULTS: In this study, we found that METH might induce the upregulation of adenosine receptor subtype 2A (A2AR), leading to glycogen synthase kinase-3 beta (GSK3β) activation and Tau phosphorylation in BBB endothelial cells. Chronic METH exposure induced BBB breakdown and anxiety- and depression-like behavioral abnormalities. Pharmacological inhibition of A2AR and GSK3β activation alleviated p-Tau accumulation, mitigated the behavioral changes, and alleviated BBB destruction induced by METH. Moreover, genetically knocking out Tau also attenuated BBB destruction and behavioral changes induced by chronic METH.

DISCUSSION: Based on these findings, we propose an A2AR-GSK3β signaling-dependent mechanism to elucidate METH-induced BBB breakdown. We suggest p-Tau as a promising candidate target to reduce BBB destruction and behavioral abnormalities in METH abusers.