Methamphetamine inhibits huntingtin-associated protein 1-mediated tyrosine receptor kinase B endocytosis resulting the neuroprotective dysfunction of brain-derived neurotrophic factor.

Abstract

Methamphetamine (METH), a synthetic stimulant, has seen an escalating abuse situation globally over the past decade. Although the molecular mechanism underlying METH-induced neurotoxicity has been explored, the dysfunction of brain-derived neurotrophic factor (BDNF) neuroprotection in the context of METH neurotoxicity remains insufficiently understood. Our previous studies have found that METH induced neurotoxicity and BDNF expression in rat primary neurons, necessitating further research into this paradox. Specifically, BDNF-dependent tyrosine receptor kinase B (TrkB) endocytosis was crucial for BDNF to confer neuroprotection in neurons. Therefore, we investigated the effect and molecular mechanism of METH on TrkB endocytosis. This work attempted to explain the potential reasons why BDNF did not exert neuroprotection in the context of METH exposure. In the current study, excessive apoptosis, elevated BDNF and reduced huntingtin-associated protein 1 (HAP1) expression were observed in the hippocampus of METH users. METH also induced cell degeneration, cytotoxicity, and BDNF expression and release in HT-22 cells in both a concentration- (0.25, 0.5, 1, 2, and 4 mM) and time-dependent manner (3, 6, 12, 24, and 48 h). Furthermore, following 24 h of exposure to METH (2 mM), apoptosis, impaired TrkB endocytosis, and reduced HAP1 expression were evident in HT-22 cells and organotypic hippocampal slices from mice. Notably, overexpression of HAP1 attenuated METH-induced cell degeneration, cytotoxicity, apoptosis, and TrkB endocytosis disruption in HT-22 cells. These findings suggest that HAP1 is a key molecule in the disruption of BDNF-mediated neuroprotective signaling by METH, and that targeting HAP1-mediated TrkB endocytosis may represent a promising therapeutic avenue for METH-induced neurotoxicity.