The regulation of p53 up‐regulated modulator of apoptosis by <scp>JNK</scp>/c‐Jun pathway in β‐amyloid‐induced neuron death

Akhter, Rumana; Sanphui, Priyankar; Das, Hrishita; Saha, Papita; Biswas, Subhas C.

doi:10.1111/jnc.13128

Cited by 72 publications

(49 citation statements)

References 63 publications

(92 reference statements)

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“…The increase in Puma expression and appearance of the second band occurred to a similar extent in Caspase-9 knockout cultures (Figure S3C), which are protected from degeneration (Simon et al, 2012), indicating that both the rise of overall Puma levels and the appearance of the second band are not simply a secondary consequence of the degenerative process. Pharmacological inhibition of JNK prevented this TD-induced rise in Puma (Figure 4E), consistent with a known role of c-Jun in promoting Puma expression (Akhter et al, 2015) and providing a mechanism for the somatic requirement for JNK signaling that we observed (Figure 2G,H). Puma has also been identified as a transcriptional target of Foxo3a (You et al, 2006), and accordingly we found that shRNA-mediated knockdown of Foxo3a in sensory neurons largely blocked the rise in Puma levels that accompanies TD (Figure 4F).…”

Section: Resultssupporting

confidence: 87%

Axon Degeneration Gated by Retrograde Activation of Somatic Pro-apoptotic Signaling

Simon

Pitts

Hertz

et al. 2016

Cell

111

177

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During development, sensory axons compete for limiting neurotrophic support, and local neurotrophin insufficiency triggers caspase-dependent axon degeneration. The signaling driving axon degeneration upon local deprivation is proposed to reside within axons. Our results instead support a model in which, despite the apoptotic machinery being present in axons, the cell body is an active participant in gating axonal caspase activation and axon degeneration. Loss of trophic support in axons initiates retrograde activation of a somatic pro-apoptotic pathway, which in turn is required for distal axon degeneration via an anterograde pro-degenerative factor. At a molecular level, the cell body is a convergence point of two signaling pathways whose integrated action drives upregulation of pro-apoptotic Puma, which, unexpectedly, is confined to the cell body. Puma then overcomes inhibition by pro-survival Bcl-xL and Bcl-w and initiates the anterograde pro-degenerative program, highlighting the role of the cell body as an arbiter of large-scale axon removal.

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Section: Resultssupporting

confidence: 87%

Axon Degeneration Gated by Retrograde Activation of Somatic Pro-apoptotic Signaling

Simon

Pitts

Hertz

et al. 2016

Cell

111

177

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“…The formation of amyloid plaques is a major factor in AD, thus, determining the underlying mechanism by which Aβ induces neuronal cell death is crucial. A recent study demonstrated that dying cells in AD brains and cultures of neurons exposed to Aβ exhibit the characteristics of apoptosis (2). However, the specific signaling pathways by which Aβ triggers cell apoptosis have not been well defined.…”

Section: Introductionmentioning

confidence: 99%

Hyperlipidemia-induced apoptosis of hippocampal neurons in apoE(−/−) mice may be associated with increased PCSK9 expression

Zhao¹,

Wu²,

Peng³

et al. 2016

Molecular Medicine Reports

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Hyperlipidemia is a risk factor for Alzheimer's disease (AD) and other neurodegenerative diseases. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a lipid regulatory gene involved in cell apoptosis. However, the function and mechanism of PCSK9 in neuronal apoptosis following hyperlipidemia remains to be elucidated. The present study established a hyperlipidemic mouse model by feeding a high-fat diet (HFD) to 6-week-old apoE(−/−) mice. Plasma lipid levels, hippocampal lipid accumulation, hippocampal histology, and hippocampal neuronal apoptosis were all monitored for changes. The expression levels of PCSK9, β-secretase 1 (BACE1), B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), and caspase-3 in hippocampal CA3 and CA1 neurons were also measured. Results demonstrated that a HFD increased the lipid accumulation in the CA3 hippocampus and the levels of plasma lipids, including triglycerides, total cholesterol, low-density lipoprotein, and high-density lipoprotein. In addition, CA3 neurons in the HFD group indicated apparent injuries and increased neuronal apoptosis, which are associated with the expression of Bcl-2, Bax, and caspase-3. A HFD also increased the expression levels of PCSK9 and BACE1. BACE1 promotes cleavage of amyloid precursor proteins to generate β-amyloid peptide (Aβ), which induces neuronal apoptosis. Protein levels of Aβ are associated with the observation of amyloid plaques in the hippocampus of the HFD group. The results suggest that hyperlipidemia regulates neuronal apoptosis by increasing PCSK9 and BACE1 expression. Overall, the current study may elucidate the role of lipid metabolism disorder in AD pathogenesis.

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“…Many studies have indicated that Aβ is toxic to neurons [22–24]. Our previous study has shown that the hASC extract promotes cell survival in a model of mutant Huntingtin-induced cell death [25].…”

Section: Resultsmentioning

confidence: 99%

Cytosolic Extract of Human Adipose Stem Cells Reverses the Amyloid Beta-Induced Mitochondrial Apoptosis via P53/Foxo3a Pathway

et al. 2017

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Human adipose stem cells (hASC) have therapeutic potential for the treatment of neurodegenerative disorders. Mitochondrial dysfunction is frequently observed in most neurodegenerative disorders, including Alzheimer’s disease. We explored the therapeutic potential of hASC cytosolic extracts to attenuate neuronal death induced by mitochondrial dysfunction in an Alzheimer’s disease (AD) in vitro models. Amyloid beta (Aβ) was used to induce cytotoxity in an immortal hippocampal cell line (HT22) and neuronal stem cells from the brain of TG2576 transgenic mice were also used to test the protective role of hASC cytosolic extracts. Cell viability and flow cytometry results demonstrated that the hASC extract prevents the toxicity and apoptosis in AD in vitro models. Moreover, JC-1 and MitoSoxRed staining followed by fluorescence microscopy and flow cytometry results showed that the hASC extract ameliorated the effect of Aβ-induced mitochondrial oxidative stress and reduced the mitochondrial membrane potential. Western blot result showed that hASC extract modulated mitochondria-associated proteins, such as Bax and Bcl2, and down-regulated cleaved caspase-3. In addition, hASC extract decreased Aβ generation and reversed up-regulated p53 and foxo3a protein level in AD in vitro model cell derived from TG2576 mice. Taken together, these findings implicate a protective role of the hASC extract in the Aβ-induced mitochondrial apoptosis via regulation of P53/foxo3a pathway, providing insight into the molecular mechanisms of hASC extract and a therapeutic strategy to ameliorate neuronal death induced by Aβ.

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The regulation of p53 up‐regulated modulator of apoptosis by JNK/c‐Jun pathway in β‐amyloid‐induced neuron death

Abstract: Neuronal loss in selective areas of brain underlies the pathology

Cited by 72 publications

References 63 publications

Axon Degeneration Gated by Retrograde Activation of Somatic Pro-apoptotic Signaling

Axon Degeneration Gated by Retrograde Activation of Somatic Pro-apoptotic Signaling

Hyperlipidemia-induced apoptosis of hippocampal neurons in apoE(−/−) mice may be associated with increased PCSK9 expression

Cytosolic Extract of Human Adipose Stem Cells Reverses the Amyloid Beta-Induced Mitochondrial Apoptosis via P53/Foxo3a Pathway

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