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 (Aβ) in primary hippocampal neurons, while the activation of autophagy dramatically ameliorated the high levels of these pathological proteins. Interestingly, after the Meth treatment, Aβ 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, Aβ, beta-secretase (Bace-1), and C-terminal fragments (CTFs). Immunofluorescence assays showed that Stx17 retarded the Meth-induced Aβ, 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.
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.
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