Erythropoietin protects PC12 cells from β-amyloid25–35-induced apoptosis via PI3K/Akt signaling pathway

Ma, Rong; Xiong, Nian; Huang, Cheng-Fang; Tang, Qiang; Hu, Benrong; Xiang, Jizhou; Li, Gang

doi:10.1016/j.neuropharm.2009.02.006

Cited by 88 publications

(72 citation statements)

References 43 publications

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“…Although several works have been reported in studying its role in Aβ toxicity, the conclusions remained controversial. In vitro studies show that application of Aβ42 reduced Akt activity, and consequently, elevated Akt activity is capable of reducing Aβ42-induced cell death in culture (26). However, another study showed that acute exposure of primary mouse neurons to Aβ42 up-regulated Akt phosphorylation (27).…”

Section: Discussionmentioning

confidence: 99%

PI3 kinase signaling is involved in Aβ-induced memory loss in Drosophila

Chiang

Wang

Xie³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

111

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Multiple intracellular signals are altered in Alzheimer's disease brain tissues, including the PI3K/Akt pathway. However, the pathological relevance of such alterations is poorly understood. In vitro studies yield results that seem to be consistent with the conventional perception in which an up-regulation of the cell survival pathway, PI3K pathway, is protective in Alzheimer's disease pathogenesis. The current in vivo genetic approach, however, reveals that inhibition of the PI3K pathway leads to rescuing of the β-amyloid peptide (Aβ)-induced memory loss in the Drosophila brain. We began our inquiry into the molecular basis of this memory loss by studying Aβ42-induced enhancement of long-term depression. We found that long-term depression is restored to a normal level through inhibition of PI3K activity. Aβ42-induced PI3K hyperactivity is directly confirmed by immunostaining of the PI3K phosphorylation targets, phospholipids. Such observations lead to the following demonstration that Aβ42-induced memory loss can be rescued through genetic silencing or pharmacological inhibition of PI3K functions. Our data suggest that Aβ42 stimulates PI3K, which in turn causes memory loss in association with an increase in accumulation of Aβ42 aggregates.

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Section: Discussionmentioning

confidence: 99%

PI3 kinase signaling is involved in Aβ-induced memory loss in Drosophila

Chiang

Wang

Xie³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

111

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“…The MTT colorimetric assay was used to evaluate the effect of VEGF gene transfection on the proliferation of HUMSCs. 39,40 The coexpression of VEGF (mouse monoclonal antibody, Millipore, Billerica, MA, USA) and EGFP was observed under a confocal microscope by immunofluorescent staining. VEGF secretion from HUMSCs into culture medium and striatal VEGF levels were spectrophotometrically measured at 450 and 570 nm by an enzyme-linked immunosorbent assay kit according to the manufacturer's instructions (R&D Systems, Minneapolis, MN, USA).…”

Section: Adenovirus Infectionmentioning

confidence: 99%

VEGF-expressing human umbilical cord mesenchymal stem cells, an improved therapy strategy for Parkinson’s disease

et al. 2010

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The umbilical cord provides a rich source of primitive mesenchymal stem cells (human umbilical cord mesenchymal stem cells (HUMSCs)), which have the potential for transplantation-based treatments of Parkinson's Disease (PD). Our pervious study indicated that adenovirus-associated virus-mediated intrastriatal delivery of human vascular endothelial growth factor 165 (VEGF 165) conferred molecular protection to the dopaminergic system. As both VEGF and HUMSCs displayed limited neuroprotection, in this study we investigated whether HUMSCs combined with VEGF expression could offer enhanced neuroprotection. HUMSCs were modified by adenovirus-mediated VEGF gene transfer, and subsequently transplanted into rotenone-lesioned striatum of hemiparkinsonian rats. As a result, HUMSCs differentiated into dopaminergic neuron-like cells on the basis of neuron-specific enolase (NSE) (neuronal marker), glial fibrillary acidic protein (GFAP) (astrocyte marker), nestin (neural stem cell marker) and tyrosine hydroxylase (TH) (dopaminergic marker) expression. Further, VEGF expression significantly enhanced the dopaminergic differentiation of HUMSCs in vivo. HUMSC transplantation ameliorated apomorphine-evoked rotations and reduced the loss of dopaminergic neurons in the lesioned substantia nigra (SNc), which was enhanced significantly by VEGF expression in HUMSCs. These findings present the suitability of HUMSC as a vector for gene therapy and suggest that stem cell engineering with VEGF may improve the transplantation strategy for the treatment of PD.

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“…EPO has the same characteristics as other neurotrophic factors, because EPO is neuroprotective in neural cells exposed to cytokines, such as tumor necrosis factor-␣ (Pregi et al, 2009), or toxins such as the A␤ amyloid peptide (Ma et al, 2009). The EPOR that mediates neuroprotection in brain is the same classical EPOR expressed in peripheral tissues (Um et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Drug Targeting of Erythropoietin Across the Primate Blood-Brain Barrier with an IgG Molecular Trojan Horse

Boado¹,

Hui²,

Lu³

et al. 2010

J Pharmacol Exp Ther

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Erythropoietin (EPO) is a neurotrophic factor that could be developed as a new drug for brain disorders. However, EPO does not cross the blood-brain barrier (BBB). In the present study, human EPO was re-engineered by fusion to the carboxyl terminus of the heavy chain of a chimeric monoclonal antibody (MAb) to the human insulin receptor (HIR). The HIRMAb acts as a molecular Trojan horse to ferry the EPO into the brain via receptor-mediated transport on the endogenous BBB insulin receptor. The HIRMAb-EPO fusion protein was immunoreactive with antibodies to both human IgG and EPO. The HIRMAb-EPO fusion protein bound with high affinity to the extracellular domain of both the HIR (ED 50 ϭ 0.21 Ϯ 0.05 nM) and the EPO receptor (ED 50 ϭ 0.30 Ϯ 0.01 nM) and activated thymidine incorporation into human TF-1 cells with an ED 50 of 0.1 nM.Differentially radiolabeled EPO and the HIRMAb-EPO fusion protein were injected intravenously into adult rhesus monkeys. Whereas EPO did not cross the primate BBB, the HIRMAb-EPO fusion protein was rapidly transported into brain, at levels that produce pharmacologic elevations in brain EPO at small systemic doses. The HIRMAb fusion protein selectively targeted the brain relative to peripheral organs. In conclusion, a novel IgG-EPO fusion protein has been engineered, expressed, and shown to be bifunctional with retention of high-affinity binding to both the insulin and EPO receptors. The IgG-EPO fusion protein represents a new class of EPO neurotherapeutics that has been specifically re-engineered to penetrate the human BBB.

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Erythropoietin protects PC12 cells from β-amyloid25–35-induced apoptosis via PI3K/Akt signaling pathway

Cited by 88 publications

References 43 publications

PI3 kinase signaling is involved in Aβ-induced memory loss in Drosophila

PI3 kinase signaling is involved in Aβ-induced memory loss in Drosophila

VEGF-expressing human umbilical cord mesenchymal stem cells, an improved therapy strategy for Parkinson’s disease

Drug Targeting of Erythropoietin Across the Primate Blood-Brain Barrier with an IgG Molecular Trojan Horse

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