Bcl-2 Prevents Killing of Neuronal Cells by Glutamate but Not by Amyloid β Protein

Behl, Christian; Hovey, Lawrence R.; Krajewski, S.; Schubert, David; Reed, John C.

doi:10.1006/bbrc.1993.2571

Cited by 95 publications

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“…In a previous study, overexpression of bcl-2 did not inhibit A␤ [25][26][27][28][29][30][31][32][33][34][35] -induced death of PC12 cells or of human neuroblastoma IMR-5 cells (58). Cell death was assessed by the MTT assay, however, which has been shown to be an inaccurate indicator of cell death induced by A␤ (59,60).…”

Section: Discussionmentioning

confidence: 99%

Multiple Pathways of Apoptosis in PC12 Cells

Ivins¹,

Ivins

Sharp³

et al. 1999

Journal of Biological Chemistry

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Stable transfectants of PC12 cells expressing bcl-2 or crmA were generated and tested for their susceptibility to various apoptotic insults. Bcl-2 expression conferred resistance to apoptosis induced by staurosporine and by oxidative insults including hydrogen peroxide and peroxynitrite, but was less effective in inhibition of activation-induced programmed cell death induced by concanavalin A. Concanavalin A-induced apoptosis was abated, however, in cells expressing very high levels of bcl-2. In contrast, cells expressing crmA were protected from concanavalin A-induced apoptosis, but were as susceptible as control cells to apoptosis induced by staurosporine and oxidative insults. Therefore, at least two apoptotic pathways in PC12 cells can be discerned by their differential sensitivity to blockade by bcl-2 and crmA. The ability of ␤-amyloid (A␤) to induce apoptosis in these cells was assessed. CrmA transfectants were protected from apoptosis induced by A␤ 1-42 , but only cells expressing very high levels of bcl-2 were similarly protected. These results suggest that the apoptotic pathway activated by A␤ 1-42 in PC12 cells can be differentiated from the apoptotic pathway activated by oxidative insults. Gene transfer experiments also demonstrated that expression of crmA in primary cultures of hippocampal neurons is protective against cell death induced by A␤ 1-42 . Together these results support the hypothesis that A␤-induced apoptosis occurs through activation-induced programmed cell death. Alzheimer's disease (AD)1 is characterized by a pronounced loss of neurons in susceptible regions of the brain (1). Evidence suggests that this neuronal loss occurs through apoptosis (2, 3), a type of cell death with distinct morphological and biochemical characteristics. The principle component of senile plaques in AD brain is ␤-amyloid (A␤), a 39 -43-amino acid peptide derived from amyloid precursor protein. A␤ has been shown to be neurotoxic in vivo (4) and in vitro (5-8), and is generally believed to contribute to the etiology of AD. Understanding how A␤ induces neuronal apoptosis, therefore, may be important for clinical interventions in AD.A␤ must aggregate into a ␤-pleated sheet structure to induce the death of cultured hippocampal neurons (6), and A␤ is not toxic when immobilized as a neuronal substrate (9). These findings have led to the suggestion that aggregated A␤ might cross-link transmembrane plasma membrane receptors to initiate a death program, in a type of activation-induced programmed cell death (APCD) (10). Studies of A␤ effects on cells have documented changes in tyrosine phosphorylation of cellular substrates (11,12), suggesting that activation of signal transduction pathways might also be involved. Because A␤ causes oxidative stress in neurons, A␤ has been proposed to cause death through an oxidative mechanism (13), and antioxidants have sometimes (13) but not always (14) been reported to block A␤-induced cell death. Other studies have suggested that A␤ perturbs calcium homeostasis in neurons to cause cell...

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Section: Discussionmentioning

confidence: 99%

Multiple Pathways of Apoptosis in PC12 Cells

Ivins¹,

Ivins

Sharp³

et al. 1999

Journal of Biological Chemistry

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“…Cells and Metabolic Labeling-The preparation, characterization, and maintenance in culture of Bcl-2-transfected and Neo-control cell lines have been described previously (12)(13)(14)(15)(16). For L-[…”

Section: Methodsmentioning

confidence: 99%

Overexpression of the Bcl-2 Protein Increases the Half-life of p21Bax

Miyashita¹,

Kitada²,

Krajewski³

et al. 1995

Journal of Biological Chemistry

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“…were rapidly down-regulated after glutamate incubation. In this regard, Bcl-2 overexpression in the central nervous system has been shown to protect cells from glutamate toxicity (Behl et al, 1993;Lawrence et al, 1996;Howard et al, 2002).…”

Section: Modulation Of Bad By Tudca 849mentioning

confidence: 99%

The Bile Acid Tauroursodeoxycholic Acid Modulates Phosphorylation and Translocation of Bad via Phosphatidylinositol 3-Kinase in Glutamate-Induced Apoptosis of Rat Cortical Neurons

Castro¹,

Solá²,

Ramalho³

et al. 2004

J Pharmacol Exp Ther

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Neurotoxicity associated with increased glutamate release results in cell death through both necrotic and apoptotic processes. In addition, tauroursodeoxycholic acid (TUDCA), an endogenous bile acid, is a strong modulator of apoptosis in several cell types. The aims of this study were to test the hypothesis that TUDCA reduces the apoptotic threshold induced by glutamate in rat cortical neurons and examine potential transduction pathways involved in both apoptotic signaling and neuroprotection by TUDCA. The results demonstrated that exposure of cortical neurons to glutamate induced cytochrome c release and caspase activation, as well as morphologic changes of apoptosis. These events were associated with down-regulation of antiapoptotic members of the Bcl-2 family,

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Bcl-2 Prevents Killing of Neuronal Cells by Glutamate but Not by Amyloid β Protein

Cited by 95 publications

References 0 publications

Multiple Pathways of Apoptosis in PC12 Cells

Multiple Pathways of Apoptosis in PC12 Cells

Overexpression of the Bcl-2 Protein Increases the Half-life of p21Bax

The Bile Acid Tauroursodeoxycholic Acid Modulates Phosphorylation and Translocation of Bad via Phosphatidylinositol 3-Kinase in Glutamate-Induced Apoptosis of Rat Cortical Neurons

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