Amyloid-beta oligomers induce Parkin-mediated mitophagy by reducing Miro1

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease associated with the accumulation of amyloid-beta oligomers (AβOs). Recent studies have demonstrated that mitochondria-specific autophagy (mitophagy) contributes to mitochondrial quality control by selectively eliminating the dysfunctional mitochondria. Mitochondria motility, which is regulated by Miro1, is also associated with neuronal cell functions. However, the role played by Miro1 in the mitophagy mechanism, especially relative to AβOs and neurodegenerative disorders, remains unknown. In this study, AβOs induced mitochondrial dysfunction, enhanced Parkin-mediated mitophagy, and reduced mitochondrial quantities in hippocampal neuronal cells (HT-22 cells). We demonstrated that AβO-induced mitochondrial fragmentation could be rescued to the elongated mitochondrial form and that mitophagy could be mitigated by the stable overexpression of Miro1 or by pretreatment with N-acetylcysteine (NAC)-a reactive oxygen species (ROS) scavenger-as assessed by immunocytochemistry. Moreover, using time-lapse imaging, under live cell-conditions, we verified that mitochondrial motility was rescued by the Miro1 overexpression. Finally, in HT-22 cells from amyloid precursor protein (APP)/presenilin 1 (PS1)/Tau triple-transgenic mice, we noted that the co-localization between mitochondria and LC3B puncta increased. Taken together, these results indicated that upregulated ROS, induced by AβO, increased the degree of mitophagy and decreased the Miro1 expression levels. In contrast, the Miro1 overexpression ameliorated AβO-mediated mitophagy and increased the mitochondrial motility. In AD model mice, AβOs induced mitophagy in the hippocampus. Thus, our results would improve our understanding of the role of mitophagy in AD toward facilitating the development of novel therapeutic agents for the treatment of AβO-mediated diseases.

Exosomes Derived From M2 Microglia Cells Attenuates Neuronal Impairment and Mitochondrial Dysfunction in Alzheimer’s Disease Through the PINK1/Parkin Pathway

“…Therefore, we examined the mitochondrial function of cells in the AD model. Consistent with another previous study ( Kam et al, 2020 ), we also found that MMP was greatly reduced in the AD model based on JC-1 staining when compared to the control group. In addition, intracellular ROS was mainly generated in mitochondria, and dysfunctional mitochondria can cause disproportionate ROS generation.…”

“…In addition, intracellular ROS was mainly generated in mitochondria, and dysfunctional mitochondria can cause disproportionate ROS generation. Further, previous studies have shown that ROS levels in neuronal cells are upregulated in AD ( Butterfield and Halliwell, 2019 ; Kam et al, 2020 ). Our results demonstrated that Aβ treatment can stimulate both intracellular and mitochondrial ROS production.…”

“…Increasing evidence has revealed that abnormal mitophagy occurs in the brains of patients with AD. Both in vitro and in vivo studies have confirmed that Aβ can disrupt the dynamics of mitophagy ( Kam et al, 2020 ; Chen et al, 2021 ). Consistent with other studies ( Kam et al, 2020 ; Sun et al, 2020 ), we found that the expression of the mitophagy markers LC3II and beclin1 increased in the AD model, according to Western blot analysis.…”

“…In neural cells, PINK1/Parkin mediated signaling is the most dominant signaling pathway of mitophagy. Besides, Kam et al found that the expression level of Parkin was enhanced in the hippocampi of 3 × Tg mice with AD ( Kam et al, 2020 ). Consistent with their findings, we also observed overexpression of PINK1 and Parkin in the AD cell model and 7-month-old APP/PS1 mice, as determined by Western blot and immunofluorescence analyses, while the administration of M2-EXOs decreased their expression in a dose-dependent manner.…”

The Protective Role of E-64d in Hippocampal Excitotoxic Neuronal Injury Induced by Glutamate in HT22 Hippocampal Neuronal Cells

“…To investigate possible changes in Cytc, Drp1, Hsc70, and Lamp2a in the context of glutamate-induced neuronal excitotoxicity, we performed immunocytochemistry according to a previous study [ 54 ]. Cells (1 × 10 5 ) were seeded into 24-well microplates and fixed with 4% paraformaldehyde in PBS.…”