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Severe neurological inflammation is one of the main symptoms of methamphetamine (meth)-induced brain injury. Studies have demonstrated that meth exposure facilitates neuroinflammation via Pellino E3 ubiquitin protein ligase 1 (Peli1)-mediated signaling. However, the involved mechanisms remain incompletely understood. Herein, we used Peli1 -/- mice and Peli1-knockdown microglial BV2 cells to decipher the roles of Peli1 and downstream signaling in meth-induced neuroinflammation. After meth administration for seven consecutive days, Peli1 -/- mice exhibited better learning and memory behavior and dramatically lower interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6 levels than wild-type mice. Moreover, in vitro experiments revealed that Peli1 knockdown significantly attenuated the meth-induced upregulation of cytokines. Besides, meth markedly activated and increased the levels of receptor-interacting protein kinase 1 (RIPK1), and Peli1 knockout or knockdown prevented these effects, indicating that RIPK1 participated in meth-induced Peli1-mediated inflammation. Specifically, treating the cells with necrostatin-1(Nec-1), an antagonist of RIPK1, remarkably inhibited the meth-induced increase in IL-1β, TNF-α, and IL-6 expression, confirming the involvement of RIPK1 in Peli1-mediated neuroinflammation. Finally, meth induced a dramatic transfer of the mixed lineage kinase domain-like protein, a downstream effector of RIRK1, to the cell membrane, disrupting membrane integrity and causing cytokine excretion. Therefore, targeting the Peli1-RIPK1 signaling axis is a potentially valid therapeutic approach against meth-induced neuroinflammation.

Methamphetamine (Meth), a central nervous system (CNS) stimulant with strong neurotoxicity, causes progressive cognitive impairment with characterized neurodegenerative changes. However, the mechanism underlying Meth-induced pathological changes remains poorly understood. In the current study, Meth elicited a striking accumulation of the pathological proteins hyperphosphorylated tau (p-tau) and amyloid beta (A β ) in primary hippocampal neurons, while the activation of autophagy dramatically ameliorated the high levels of these pathological proteins. Interestingly, after the Meth treatment, A β was massively deposited in autophagosomes, which were remarkably trapped in early endosomes. Mechanistically, syntaxin 17 (Stx17), a key soluble n-ethylmaleimide-sensitive fusion protein (NSF) attachment protein receptor (SNARE) protein responsible for autophagosome and mature endosome/lysosome fusion, was significantly downregulated and hindered in combination with autophagosomes. Notably, adenovirus overexpression of Stx17 in primary neurons facilitated autophagosome-mature endosome/lysosome fusion, which dramatically reversed the Meth-induced increases in the levels of p-tau, A β , beta-secretase (Bace-1), and C-terminal fragments (CTFs). Immunofluorescence assays showed that Stx17 retarded the Meth-induced A β , p-tau, and Bace-1 accumulation in autophagosomes and facilitated the translocation of these pathological proteins to lysosomes, which indicated the importance of Stx17 via enhanced autophagosome-mature endosome/lysosome fusion. Therefore, the current study reveals a novel mechanism involving Meth-induced high levels of pathological proteins in neurons. Targeting Stx17 may provide a novel therapeutic strategy for Meth-induced neurodegenerative changes., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2022 Yuanhui Zhu et al.)

Methamphetamine (METH), a psychoactive-stimulant facilitates massive accumulation of autophagosomes and causes autophagy-associated neuronal death. However, the underlying mechanisms involving METH-induced auto-phagosome accumulation remain poorly understood. In the current study, autophagic flux was tracked by mRFP-GFP-LC3 adenovirus, 900 μM METH treatment was found to significantly disrupt autophagic flux, which was further validated by remarkable increase of co-localized of LC3 and SQSTM1/p62, enhancement of LC3-II and SQSTM1/p62 protein levels, and massive autophagosome puncta aggregation. With the cycloheximide (CHX) treatment, METH treatment was displayed a significant inhibition of SQSTM1/p62 degradation. Therefore, the mRNAs associated with vesicle degradation were screened, and syntaxin 17 (Stx17) and dynein-dynactin mRNA levels significantly decreased, an effect was proved in protein level as well. Intriguingly, METH induced autophagosome accumulation and autophagic flux disturbance was incredibly retarded by overexpression of Stx17, which was validated by the restoration of the fusion autophagosome-late endosome/lysosome fusion. Moreover, Stx17 overexpression obviously impeded the METH-induced decrease of co-localization of the retrograded motor protein dynein/dynactin and autophagosome-late endosome, though the dynein/dynactin proteins were not involved in autophagosome-late endosome/lysosome fusion. Collectively, our findings unravel the mechanism of METH-induced autophagosome accumulation involving autophagosome-late endosome/lysosome fusion deficiency and that autophagy-enhancing mechanisms such as the overexpression of Stx17 may be therapeutic strategies for the treatment of METH-induced neuronal damage., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Methamphetamine (Meth), a highly addictive drug, can induce irreversible neuronal damage and cause neuropsychiatric and cognitive disorders. Meth's effects on modulating microglial neuroimmune functions and eliciting neuroinflammation have attracted considerable attention in recent years. Recent evident of the effect of the non-dependent domain containing adaptor inducing interferon (TRIF)/Pellino1 (Peli1) signaling axis on pro-inflammatory cytokine production provides novel clues for inflammation. Therefore, our study investigated Meth-induced neurotoxicity from a neuropathological perspective by examining TLR4-TRIF-Peli1 axis signaling activation. Meth significantly activated microglia accompanied by marked increase of TLR4 and TRIF expression, NF-kB and MAPK pathways activation and the production of IL-1β, TNF-α and IL-6. Peli1 was involved in Meth-mediated neuroinflammation and knockdown of Peli1 strongly reversed NF-kB and MAPK pathways activation and pro-inflammatory cytokine excretion. Intriguingly, Peli1 upregulation induced by Meth was dependent on TRIF rather than the myloid differentiation factor 88 (MyD88) pathway, since the silencing of TRIF significantly suppressed Meth-induced Peli1 upregulation, while MyD88 knockdown had no obvious impact. Additionally, an in vivo study verified TLR4-TRIF-Peli1 axis activation and an enhanced level of downstream cytokine expression in the cortex after Meth treatment. Therefore, these findings provide new insight regarding the specific contributions of the TRIF-Peli1 pathway to Meth-mediated neuroinflammation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Methamphetamine (METH), an amphetamine-like drug, is one of the most commonly used central nervous system psychostimulants worldwide. METH abuse frequently leads to cognitive decline and dementia-like changes, but the mechanisms remain poorly understood. In the present study, the mechanisms of METH-induced changes in Alzheimer's disease-like pathological protein in Neuro2A cells were explored. Our results indicated that METH exposure significantly increased the expression of the pathological protein hyperphosphorylated tau (p-tau). Further analysis revealed that METH exposure obviously disrupted insulin signalling, resulted in brain insulin resistance, which manifested as downregulation of the insulin receptor substrate-1, AKT ser 473 , and GSK3β activation. Notably, the linkage between p-tau expression and insulin signalling can be partially verified by treatment with the insulin-sensitizing drug rosiglitazone and GSK3β inhibitor TWS119 which specifically reversed METH-induced hyperphosphorylation of tau. Our results indicate that insulin signalling can be therapeutically exploited for attenuating METH-induced upregulation of p-tau., (Copyright © 2018. Published by Elsevier B.V.)