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: R inhibiton, GSK3β inhibition or p-Tau knockout. Results: R 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: R-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.