Pathological methamphetamine exposure triggers the accumulation of neuropathic protein amyloid-β by inhibiting UCHL1

Neurotoxicology. 2021 Sep:86:19-25. doi: 10.1016/j.neuro.2021.06.004. Epub 2021 Jun 24.

Abstract

Methamphetamine (METH), a powerful psychoactive drug, causes damage to the nervous system and leads to degenerative changes similar to Alzheimer's disease (AD), however, the molecular mechanism between the toxicity of METH and AD-related symptoms remains poorly understood. In this study, we investigated the effect of METH exposure on the accumulation of amyloid-β by establishing the animal and cell models. The results showed that METH exposure increased amyloid precursor protein (APP) and β-secretase (BACE1), contributed to the accumulation of amyloid-β, and which was alleviated with the pretreatment of BACE1 inhibitor. In addition, METH exposure decreased ubiquitin carboxy-terminal hydrolases L1 (UCHL1) which was related to the degradation of BACE1, and therefore led to the up-regulation of BACE1. In summary, the study could provide a new insight into the molecular mechanisms of METH toxicity and new evidence for the link between METH abuse and AD.

Keywords: Alzheimer's disease; Amyloid-β; BACE1; Methamphetamine; UCHL1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Cells, Cultured
  • Central Nervous System Stimulants / toxicity*
  • Dose-Response Relationship, Drug
  • Male
  • Methamphetamine / toxicity*
  • Mice
  • Mice, Inbred C57BL
  • Neurons / drug effects
  • Neurons / metabolism
  • Peptide Fragments / metabolism*
  • Ubiquitin Thiolesterase / antagonists & inhibitors*
  • Ubiquitin Thiolesterase / metabolism*

Substances

  • Amyloid beta-Peptides
  • Central Nervous System Stimulants
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • Methamphetamine
  • Ubiquitin Thiolesterase
  • Uchl1 protein, mouse