Staurosporine‐Induced Activation of Caspase‐3 Is Potentiated by Presenilin 1 Familial Alzheimer's Disease Mutations in Human Neuroglioma Cells

Kovacs, Dora M.; Mancini, Ronald; Henderson, John; Na, Sang J.; Schmidt, Stephen D.; Kim, Tae Wan; Tanzi, Rudolph E.

doi:10.1046/j.1471-4159.1999.0732278.x

Cited by 46 publications

(35 citation statements)

References 40 publications

(64 reference statements)

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“…Our data showing that the PS1¢9 FAD mutation potentiates caspase activation and apoptosis induced by hypocapnia, or by hypocapnia plus hypoxia are consistent with the previously reported activity of this and other PS1 FAD mutations in promoting enhanced susceptibility to apoptosis and neuronal death [17,18]. While the molecular mechanisms by which PS1 mutations enhance cell apoptosis have not been determined, several have been reported to interfere with cellular calcium homeostasis and calcium release from the ER [18,29,30] thereby promoting cell death.…”

Section: Discussionsupporting

confidence: 92%

“…These cells were previously shown to express sufficiently low levels of PS1 so as to avoid spontaneous apoptosis that can result from robust overexpression of PS1 [17]. H4 cells stably transfected with APP (H4 Swedish mutation cells) [20] were used in the experiments in which Aß levels were assayed.…”

Section: Cell Linesmentioning

confidence: 99%

“…Western blot analysis was performed as described by Kovacs et al [17]. Briefly, 40 Ìg of total protein of each sample was subjected to SDS-polyacrylamide gel electrophoresis using 4-20% gradient Tris/ glycine gels under reducing conditions (Invitrogen, Carlsbad, Calif., USA).…”

Section: Western Blot Analysis Of Caspase-3 Cleavagementioning

confidence: 99%

“…Thus, we set out to examine whether hypocapnia can contribute to AD neuropathogenesis via induction of caspase activation, apoptosis, and increased Aß production. Mutations in PS1 increase cell susceptibility to apoptosis induced by staurosporine [17] and neuronal death by hypoxia [18]. Thus, we also examined whether the PS1¢9 FAD mutation can render increased hypersensitivity to caspase-3 activation and apoptosis induced by hypocapnia.…”

Section: Introductionmentioning

confidence: 99%

“…As in Kovacs et al [17], we used stably transfected H4 human neuroglioma cells expressing a relatively low level of PS1 to minimize overexpression artifacts (e.g. spontaneous apoptosis).…”

Section: Introductionmentioning

confidence: 99%

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Hypocapnia Induces Caspase-3 Activation and Increases Aβ Production

Xie

Moir²,

Romano³

et al. 2004

Neurodegener Dis

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Background: At least half of all cases of early onset (<60) familial Alzheimer’s disease (FAD) are caused by any of over 150 mutations in three genes: the amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2). Mutant forms of PS1 have been shown to sensitize cells to apoptotic cell death. Objective: We investigated the effects of hypocapnia, a risk factor for both cognitive and neurodevelopment deficits, on caspase-3 activation, apoptosis, and amyloid β-protein (Aβ) production, and assessed the influence of the PS1Δ9 FAD mutation on these effects. Method: For this purpose, we exposed stably transfected H4 human neuroglioma cells to conditions consistent with hypocapnia (PCO₂ <40 mm Hg) and hypocapnia plus hypoxia (PO₂ <21%). Results: Hypocapnia (20 mm Hg CO₂ for 6 h) induced caspase-3 activation and apoptosis; the PS1Δ9 FAD mutation significantly potentiated these effects. Moreover, the combination of hypocapnia (20 mm Hg CO₂) and hypoxia (5%O₂) induced caspase-3 activation and apoptosis in a synergistic manner. Hypocapnia (5 and 20 mm Hg CO₂for 6 h) also led to an increased Aβ production. Conclusion: The findings suggest that hypocapnia (e.g. during general anesthesia) could exacerbate AD neuropathogenesis.

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Section: Discussionsupporting

confidence: 92%

Section: Cell Linesmentioning

confidence: 99%

Section: Western Blot Analysis Of Caspase-3 Cleavagementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…As in Kovacs et al [17], we used stably transfected H4 human neuroglioma cells expressing a relatively low level of PS1 to minimize overexpression artifacts (e.g. spontaneous apoptosis).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Hypocapnia Induces Caspase-3 Activation and Increases Aβ Production

Xie

Moir²,

Romano³

et al. 2004

Neurodegener Dis

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The Common Inhalational Anesthetic Sevoflurane Induces Apoptosis and Increases β-Amyloid Protein Levels

Dong¹,

Zhang²,

Zhang³

et al. 2009

Arch Neurol

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238

204

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Elevated vulnerability to oxidative stress‐induced cell death and activation of caspase‐3 by the Swedish amyloid precursor protein mutation

Eckert

Steiner

Marques

et al. 2001

J of Neuroscience Research

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The Swedish double mutation (KM670/671NL) of amyloid precursor protein (APPsw) is associated with early-onset familial Alzheimer's disease (FAD) and results in from three- to sixfold increased beta-amyloid production. The goal of the present study was to elucidate the effects of APPsw on mechanisms of apoptotic cell death. Therefore, PC12 cells were stably transfected with human APPsw. Here we report that the vulnerability of APPsw-bearing PC12 cells to undergo apoptotic cell death was significantly enhanced after exposure to hydrogen peroxide compared to human wild-type APP-bearing cells, empty vector-transfected cells, and parent untransfected cells. In addition, we have analyzed the potential influence of several mechanisms that can interfere with the execution of the apoptotic cell death program: the inhibition of cell death by the use of caspase inhibitors and the reduction of oxidative stress by the use of (+/-)-alpha-tocopherol (vitamin E). Interestingly, oxidative stress-induced cell death was significantly attenuated in APPsw PC12 cells by pretreatment with caspase-3 inhibitors but not with caspase-1 inhibitors. In parallel, caspase-3 activity was markedly elevated in APPsw PC12 after stimulation with hydrogen peroxide for 6 hr, whereas caspase-1 activity was unaltered. In addition, oxidative stress-induced cell death could be reduced after pretreatment of APPsw cells with (+/-)-alpha-tocopherol. The protective potency of (+/-)-alpha-tocopherol was even greater than that of caspase-3 inhibitors. Our findings further emphasize the role of mutations in the amyloid precursor protein in apoptotic cell death and may provide the fundamental basis for further efforts to elucidate the underlying processes caused by FAD-related mutations.

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Staurosporine‐Induced Activation of Caspase‐3 Is Potentiated by Presenilin 1 Familial Alzheimer's Disease Mutations in Human Neuroglioma Cells

Cited by 46 publications

References 40 publications

Hypocapnia Induces Caspase-3 Activation and Increases Aβ Production

Hypocapnia Induces Caspase-3 Activation and Increases Aβ Production

The Common Inhalational Anesthetic Sevoflurane Induces Apoptosis and Increases β-Amyloid Protein Levels

Elevated vulnerability to oxidative stress‐induced cell death and activation of caspase‐3 by the Swedish amyloid precursor protein mutation

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