Mitochondrial methionine sulfoxide reductase B2 links oxidative stress to Alzheimer's disease-like pathology

Xiang, Xian-Ling; Li, Song; Deng, Xiao‐Juan; Tang, Ying; Zhuo, Min; Luo, Biao; Wen, Qi-Xin; Li, Kunyi; Chen, Jian; Ma, Yuanlin; Zhu, Binglin; Yan, Zhen; Chen, Guojun

doi:10.1016/j.expneurol.2019.05.006

Cited by 22 publications

(15 citation statements)

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“…Although previous study demonstrates that JNK also controls BACE1 expression (Guglielmotto et al., 2011), it might be unlikely that TXN2 employs this signaling in regulating BACE1, as in endothelial cells, TXN2 controls apoptosis in a JNK‐independent manner (Zhang et al., 2004). Moreover, we have reported that JNK is also involved in APP transcription regulated by another mitochondrial protein methionine sulfoxide reductase B2 (Xiang et al., 2019), yet this study fails to show that TXN2 affects APP protein levels. TXN2 might control apoptosis through the following mechanisms: (1) TXN2 may play a role in intrinsic mitochondria‐apoptosis pathway (Hansen et al., 2006; Lu & Holmgren, 2012).…”

Section: Discussioncontrasting

confidence: 59%

“…In our study, TXN2 expression is decreased in the brain of WT and APP/PS1 mice with age, which is in line with the previous report demonstrating that TXN2 expression is significantly reduced in a rat model of mimetic aging (Sun et al., 2015). Aging is one of the most significant risk factors for AD (Hou et al., 2019); and gene expression relative to antioxidant defense system is decreased during aging (Reutzel et al., 2020; Xiang et al., 2019). Given that TXN2 also regulates the levels of ROS (Figure 4) and Aβ (Figures 1 and 2), it is tempting to speculate that TXN2 may play a role in the development of aging to AD (Müller et al., 2010).…”

Section: Discussionmentioning

confidence: 99%

“…Human neuroblastoma cells (SH‐SY5Y, RRID: CVCL_0019; The European Collection of Authenticated Cell Cultures) and human embryonic kidney 293 cell line (HEK293, RRID: CVCL_0045; American Type Culture Collection) stably express full‐length human APP (HEK‐APP) were maintained as described previously (Xiang et al., 2019). These two cell lines are not listed in the International Cell Line Authentication Committee (ICLAC) database of cross‐contaminated or misidentified cell lines.…”

Section: Methodsmentioning

confidence: 99%

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Mitochondrial TXN2 attenuates amyloidogenesis via selective inhibition of BACE1 expression

Xiang

et al. 2020

Journal of Neurochemistry

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Thioredoxin-2 (TXN2) is a mitochondrial protein and represents one of the intrinsic antioxidant enzymes. It has long been recognized that mitochondrial dysfunction and oxidative stress contribute to the pathogenesis of Alzheimer's disease (AD). We hypothesized that mitochondrial TXN2 might play a role in AD-like pathology. In this study, we found that in SH-SY5Y and HEK cells stably express full-length human amyloid-β precursor protein (HEK-APP), TXN2 silencing or over-expression selectively increased or decreased the transcription of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), respectively, without altering the protein levels of others enzymes involved in the catalytic processing of APP. As a result, β-amyloid protein (Aβ) levels were significantly decreased by TXN2. In addition, in cells treated with 3-nitropropionic acid (3-NP) that is known to increase reactive oxygen species (ROS) and promote mitochondrial dysfunction, TXN2 silencing resulted in further enhancement of BACE1 protein levels, suggesting a role of TXN2 in ROS removal. The downstream signaling might involve NFκB, as TXN2 reduced the phosphorylation of p65 and IκBα; and p65 knockdown significantly attenuated TXN2-mediated regulation of BACE1. Concomitantly, the levels of cellular ROS, apoptosis-related proteins and cell viability were altered by TXN2 silencing or over-expression. In APPswe/PS1E9 mice, an animal model of AD, the cortical and hippocampal TXN2 protein levels were decreased at 12 months but not at 6 months, suggesting an age-dependent decline.Collectively, TXN2 regulated BACE1 expression and amyloidogenesis via cellular ROS and NFκB signaling. TXN2 might serve as a potential target especially for early intervention of AD.

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Section: Discussioncontrasting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Mitochondrial TXN2 attenuates amyloidogenesis via selective inhibition of BACE1 expression

Xiang

et al. 2020

Journal of Neurochemistry

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“…Tau phosphorylation can be mediated by several kinases [ 30 ]. In this study, the active form of GSK3β (GSK3β-y216) was increased in 5xFAD mice, which was attenuated by JBPOS0101.…”

Section: Discussionmentioning

confidence: 99%

JBPOS0101 regulates amyloid beta, tau, and glial cells in an Alzheimer’s disease model

et al. 2020

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Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease characterized by cognitive dysfunction and memory loss as the main symptoms. The deposition of amyloid beta (Aβ) and tau hyperphosphorylation are hallmarks of AD and are major therapeutic targets. However, the exact etiology has not yet been fully elucidated; thus, no drug that cures the disease has been approved. JBPOS0101 is a phenyl carbamate compound that has been tested as a drug for epileptic diseases. In our previous study, we showed that JBPOS0101 attenuated the accumulation of Aβ as well as the deficits in learning and memory in the 5xFAD mouse model. Here, we tested the dose effect (70 or 35 mg/kg) of JBPOS0101 on the memory defect and pathological markers and further investigated the underlying mechanisms in 5xFAD mice. In the behavior tests, JBPOS0101 treatment ameliorated deficits in learning and memory. Moreover, JBPOS0101 attenuated Aβ accumulation and tau phosphorylation. The elevated phosphorylation levels of the active GSK3β form (GSK3β-y216) in 5xFAD, which are responsible for tau phosphorylation, decreased in the JBPOS0101-treated groups. Furthermore, the elevation of reactive astrocytes and microglia in 5xFAD mice was attenuated in JBPOS0101-treated groups. These data suggest that JBPOS0101 may be a new drug candidate to lessen amyloid- and tau-related pathology by regulating glial cells.

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“…Western blotting was performed as previously described. 15 Samples were loaded onto 8% SDS-PAGE gels. The separated proteins were transferred to 0.22 μm polyvinylidene fluoride (PVDF) membranes (Bio-Rad, Hercules, CA, USA, Cat# 162-0177).…”

Section: Western Blottingmentioning

confidence: 99%

TUFM is involved in Alzheimer’s disease‐like pathologies that are associated with ROS

Zhong

Zhou

et al. 2021

FASEB j.

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Mitochondrial Tu translation elongation factor (TUFM or EF-Tu) is part of the mitochondrial translation machinery. It is reported that TUFM expression is reduced in the brain of Alzheimer's disease (AD), suggesting that TUFM might play a role in the pathophysiology. In this study, we found that TUFM protein level was decreased in the hippocampus and cortex especially in the aged APP/PS1 mice, an animal model of AD. In HEK cells that stably express full-length human amyloid-β precursor protein (HEK-APP), TUFM knockdown or overexpression increased or reduced the protein levels of β-amyloid protein (Aβ) and β-amyloid converting enzyme 1 (BACE1), respectively. TUFM-mediated reduction of BACE1 was attenuated by transla-hydrazinylidene]-2-nitro-benzenepropanoic acid (4EGI1), and in cells overexpressing BACE1 constructs deleting the 5′ untranslated region (5′UTR). TUFM silencing increased the half-life of BACE1 mRNA, suggesting that RNA stability was affected by TUFM. In support, transcription inhibitor Actinomycin D (ActD) and silencing of nuclear factor κB (NFκB) failed to abolish TUFM-mediated regulation of BACE1 protein and mRNA. We further found that the mitochondria-targeted antioxidant TEMPO diminished the effects of TUFM on BACE1, suggesting that reactive oxygen species (ROS) played an important role. Indeed, cellular ROS levels were affected by TUFM knockdown or overexpression, and TUFM-mediated regulation of apoptosis and Tau phosphorylation at selective sites was attenuated by TEMPO. Collectively, TUFM protein levels were decreased in APP/PS1 mice. TUFM is involved in AD pathology by regulating BACE1 translation, apoptosis, and Tau phosphorylation, in which ROS plays an important role.

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Mitochondrial methionine sulfoxide reductase B2 links oxidative stress to Alzheimer's disease-like pathology

Cited by 22 publications

References 74 publications

Mitochondrial TXN2 attenuates amyloidogenesis via selective inhibition of BACE1 expression

Mitochondrial TXN2 attenuates amyloidogenesis via selective inhibition of BACE1 expression

JBPOS0101 regulates amyloid beta, tau, and glial cells in an Alzheimer’s disease model

TUFM is involved in Alzheimer’s disease‐like pathologies that are associated with ROS

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