Appoptosin is a Novel Pro-Apoptotic Protein and Mediates Cell Death in Neurodegeneration

Zhang, Han; Zhang, Yunwu; Chen, Yaomin; Huang, Xiumei; Zhou, Fangfang; Wang, Weiwei; Xian, Bo; Zhang, Xian; Masliah, Eliezer; Chen, Quan; Han, Jing; Bu, Guojun; Reed, John C.; Liao, Francesca Fang; Chen, Ye Guang; Xu, Huaxi

doi:10.1523/jneurosci.3668-12.2012

Cited by 56 publications

(64 citation statements)

References 47 publications

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“…As a primary agent in AD, amyloid-β peptide initiates the main cytopathologies of AD, such as oxidative stress, mitochondrial dysfunction, accumulation of iron in cells and so on [28][29][30][31] . Recent evidence shows that Aβ can induce intracellular heme synthesis and iron uptake in vitro [9,32] . Heme can bind to Aβ to form heme-Aβ, promoting [24,26,33,34] .…”

Section: Discussionmentioning

confidence: 99%

“…Over production and accumulation of heme in cells may exacerbate production of intracellular ROS and increase oxidative stress on cells, thus promoting cell apoptosis [21,23] . Recent studies in vitro have shown that appoptosin can induce heme biosynthesis, resulting in ROS overproduction, mitochondrial ΔΨm loss, and intrinsic caspase-dependent apoptosis, especially when cells overexpress appoptosin during 12 h to 36 h [9] . Accumulation of heme may play a key role in the pathological progress of appoptosin-induced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…Curcumin prevents cells from appoptosin-induced overproduction of intracellular ROS Intracellular ROS has been reported to play an important role in appoptosin-induced apoptosis [9] . In this study, appoptosintransfected SH-SY5Y cells were treated with 10 μmol/L curcumin or vehicle (0 μmol/L curcumin) for 24 h. ROS was then detected by flow cytometry.…”

Section: Effects Of Curcumin On Sh-sy5y Cell Viabilitymentioning

confidence: 99%

“…Appoptosin is upregulated in AD brains as well as in neurons treated with β-amyloid [9] . It belongs to the mitochondrial solute carrier family (SLC25), which is encoded by nuclear genes located on chromosome 3p22.1, synthesized in the cytosol and located in the inner mitochondrial membrane.…”

Section: Introductionmentioning

confidence: 99%

“…Appoptosin acts as a transporter that shuttles glycine into mitochondria and 5-aminolevulinic acid out of mitochondria [10,11] . Further research has found that appoptosin regulates intrinsic caspasedependent apoptosis by governing heme biosynthesis, hence inducing ROS overproduction, impairing mitochondrial www.chinaphar.com Zheng KM et al Acta Pharmacologica Sinica npg membrane potential, promoting cytochrome c release, and activating caspase 9 and caspase 3 [9] . Therefore, preventing appoptosin-induced intrinsic caspase-dependent apoptosis would be a promising therapeutic alternative in AD treatment.…”

Section: Introductionmentioning

confidence: 99%

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Curcumin inhibits appoptosin-induced apoptosis via upregulating heme oxygenase-1 expression in SH-SY5Y cells

Zheng

Zhang

et al. 2015

Acta Pharmacol Sin

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Aim: Appoptosin (SLC25A38) is a pro-apoptotic protein, which is upregulated in Alzheimer's disease (AD) brains and plays an important role in promoting the pathological progress of AD. The aim of this study was to investigate the effects of curcumin from the rhizome of Curcuma longa on appoptosin-induced apoptosis in SH-SY5Y cells. Methods: SH-SY5Y cells were pretreated with curcumin, then transfected with appoptosin or vector. The apoptotic cells were detected with Annexin V staining analysis by flow cytometry. The expression of cleaved caspase-3, appoptosin, heme oxygenase-1 (HO-1) was examined using Western blotting. Intracellular level of ROS was measured with DCFH-DA staining by flow cytometry analysis. Mitochondrial membrane potential (ΔΨm) was detected with JC-1 staining under a fluorescence microscope and quantified by fluorescence ratio detection. Results: Overexpression of appoptosin in SH-SY5Y cells markedly increased cell apoptosis accompanied by reduced HO-1 expression, increased intracellular heme level, ROS overproduction and ΔΨm impairment. Treatment of SH-SY5Y cells with curcumin (2.5-20 μmol/L) for 24 h did not significantly affect their viability. However, pretreatment with curcumin (2.5-20 μmol/L) dose-dependently attenuated all above-mentioned pathological changes in appoptosin-transfected SH-SY5Y cells. Conclusion: Curcumin inhibits appoptosin-induced apoptosis in SH-SY5Y cells by upregulating the expression of HO-1, reducing the production of intracellular heme and ROS, and preventing the ΔΨm loss.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Effects Of Curcumin On Sh-sy5y Cell Viabilitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Curcumin inhibits appoptosin-induced apoptosis via upregulating heme oxygenase-1 expression in SH-SY5Y cells

Zheng

Zhang

et al. 2015

Acta Pharmacol Sin

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Therapeutic anti‐amyloid β antibodies cause neuronal disturbances

Adhikari

Khan

Mikhael

et al. 2022

Alzheimer's & Dementia

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Recent published clinical trial safety data showed that 41% of Alzheimer patients experienced amyloid-related imaging abnormalities (ARIA), marks of microhemorrhages and oedema in the brain, following administration of Biogen's Aduhelm/ aducanumab (amino acids 3-7 of the Aβ peptide). Similarly, Janssen/Pfizer's Bapineuzumab (amino acids 1-5 of the Aβ peptide) and Roche's Gantenerumab (amino acids 2-11/18-27 of the Aβ peptide) also displayed ARIA in clinical trials, including microhemorrhage and focal areas of inflammation or vasogenic oedema respectively. The molecular mechanisms underlying ARIA caused by therapeutic anti-Aβ antibodies remain largely unknown, however, recent reports demonstrated that therapeutic antiprion antibodies activate both neuronal apoptotic and allergenic proteomes following cross-linking cellular prion protein. Here, we report that treatment of human induced pluripotent stem cellsderived neurons (HSCN) from a non-demented donor, co-cultured with human primary microglia with anti-Aβ1-6, or anti-Aβ17-23 antibodies activate a significant number of both apoptotic and allergenic-related proteins as assessed by mass spectrometry. Interestingly, a large proportion of the identified proteins included cytokines such as IL-4, IL-12, and IL-13 suggesting a type-1 hypersensitivity response. Following flow cytometry analysis, several proinflammatory cytokines were significantly elevated following anti-Aβ1-6, or anti-Aβ17-23 antibody treatment. These results justify further and more robust investigation of the molecular mechanisms of ARIA during immunotherapy study trials of AD.

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From a single nucleotide polymorphism to tau pathology: Appoptosin is the missing link

2015

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I-C, Heyser CJ, et al. Appoptosin-mediated caspase cleavage of tau contributes to progressive supranuclear palsy pathogenesis. Neuron. 2015;87:963-975. This study recently published in Neuron by Yingjun Zhao and colleagues has revealed the link between progressive supranuclear palsy (PSP) and the single-nucleotide polymorphism (SNP) rs1768208. The exciting discovery uncovers new pathogenic mechanisms upstream in the cascade of tau aggregation and opens doors for new treatment approaches.Previous studies have laid important groundwork: In 2011, a genome-wide association study identified several new SNPs associated with PSP, including the T allele of rs1768208.1 Subsequently, the latter has been linked to other tauopathies, including corticobasal degeneration, 2 Alzheimer s disease (AD), 3 and tau-positive frontotemporal lobar degeneration. 4 Although located near the myelin-associated oligodendrocyte basic protein gene in chromosome 3, rs1768208 was found to have a major influence on the expression of SLC25A38 70 kb away.1 In 2012, Zhang and colleagues characterized SLC25A38 as a proapoptotic, and ß-amyloid precursor protein-interacting protein.According to these properties, SLC25A38 was designated appoptosin. Overexpression of appoptosin resulted in caspasedependent cell apoptosis and was associated with neuronal cell death in rodent models for AD and brain ischemia.5 In PSP and other tauopathies, intracellular aggregation of hyperphosphorylated tau is considered the immediate cause of neurodegeneration.But how does appoptosin influence tau pathology? This missing piece in the puzzle has now been revealed. In brief, the group of Yingjun Zhao demonstrated that appoptosin (1) induces caspase-3-mediated tau cleavage, (2) reduces the ability of tau to bind to microtubule, (3) promotes tau aggregation, (4) causes synaptic dysfunction in neuronal cells, and (5) induces PSP-like motor dysfunction in transgenic mutant tau mice. The susceptibility of the rs1768208 T allele to PSP was confirmed by genotyping of postmortem brain samples of PSP and control patients: A significantly higher incidence of the rs1768208 T allele in PSP (77%) was found, compared with controls (32%). In cases carrying the T allele, expression of appoptosin was higher than in non-T-allele PSP and controls. Levels of appoptosin, activated caspase-3, caspasecleaved c-tau fragment, and hyperphosphorylated tau were significantly increased in the frontal cortex of PSP brains. Furthermore, the authors found increased levels and caspase-3-cleaved tau in brains of patients with AD and tau-positive frontotemporal lobar degeneration. Appoptosin transduction of rat cortical neuronal cultures resulted in elevation of caspase-3 and c-tau fragments, disabled tau to bind to microtubule, and increased levels of insoluble tau. The functional effects of appoptosin on neurons were clearly induced by tau dysfunction, because synaptotoxic effects were absent in tau-deficient neurons, and appoptosin-induced motor dysfunction was present in mutant tau transgenic mice, ...

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Appoptosin is a Novel Pro-Apoptotic Protein and Mediates Cell Death in Neurodegeneration

Cited by 56 publications

References 47 publications

Curcumin inhibits appoptosin-induced apoptosis via upregulating heme oxygenase-1 expression in SH-SY5Y cells

Curcumin inhibits appoptosin-induced apoptosis via upregulating heme oxygenase-1 expression in SH-SY5Y cells

Therapeutic anti‐amyloid β antibodies cause neuronal disturbances

From a single nucleotide polymorphism to tau pathology: Appoptosin is the missing link

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