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A General Method for Evaluating Deep Brain Stimulation Effects on Intravenous Methamphetamine Self-Administration
Published on: January 22, 2016
Endothelial adenosine A2A receptor activation-mediated Tau hyperphosphorylation leads to blood-brain barrier
Ying Qian1, Meigui Hu2, Xingxing Xie3,4
1Department of Pharmacy, Affiliated Hospital of Zunyi Medical University, Zunyi, China.
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.
Insights
Methamphetamine (METH) causes blood-brain barrier (BBB) breakdown by activating the A2A-GSK3β pathway, leading to Tau phosphorylation in endothelial cells. Inhibiting this pathway or Tau reduces BBB damage and behavioral issues.
Area of Science:
- Neuroscience
- Pharmacology
- Cell Biology
Background:
- Methamphetamine (METH) is a psychostimulant known to disrupt the blood-brain barrier (BBB).
- Previous research indicated increased phosphorylated Tau (p-Tau) in neurons post-METH exposure, but its role in endothelial cells and BBB integrity remained unclear.
Purpose of the Study:
- To investigate the mechanism of METH-induced BBB breakdown, focusing on p-Tau accumulation in endothelial cells.
- To explore the role of the adenosine receptor subtype 2A (A2AR)-glycogen synthase kinase-3 beta (GSK3β) signaling pathway in METH-induced BBB damage.
Main Methods:
- Evaluated protein levels in the A2AR-GSK3β signaling pathway in a chronic METH mouse model.
- Assessed BBB integrity, endothelial p-Tau levels, and behavioral performance after A2AR inhibition, GSK3β inhibition, or p-Tau knockout.
Main Results:
- METH upregulated A2AR, activating GSK3β and leading to Tau phosphorylation in BBB endothelial cells.
- Chronic METH exposure caused BBB breakdown and behavioral abnormalities (anxiety, depression).
- Inhibition of A2AR, GSK3β, or genetic knockout of Tau attenuated METH-induced BBB damage and behavioral deficits.
Conclusions:
- Proposed an A2AR-GSK3β signaling-dependent mechanism for METH-induced BBB breakdown.
- Identified p-Tau as a potential therapeutic target for mitigating BBB destruction and behavioral abnormalities in METH abuse.
