Characterization of V642I-AβPP-induced cytotoxicity in primary neurons
Takako Niikura, Marina Yamada, Tomohiro Chiba, Sadakazu Aiso, Masaaki Matsuoka, Ikuo Nishimoto
Amyloid precursor protein (AβPP), a precursor of amyloid β (Aβ) peptide, is one of the molecules involved in the pathogenesis of Alzheimer's disease (AD). Specific mutations in AβPP have been found in patients inheriting familial AD (FAD). These mutant AβPP proteins cause cell death in neuronal cell lines in vitro, but the molecular mechanism of cytotoxicity has not yet been clarified completely. We analyzed the cytotoxic mechanisms of the London-type AβPP mutant, V642I-AβPP, in primary cortical neurons utilizing an adenovirus-mediated gene transfer system. Expression of V642I-AβPP protein induced degeneration of the primary neurons. This cytotoxicity was blocked by pertussis toxin, a specific inhibitor for heterotrimeric G proteins, Go/i, and was suppressed by an inhibitor of caspase-3/7 and an antioxidant, glutathione ethyl ester. A specific inhibitor for NADPH oxidase, apocynin, but not a xanthine oxidase inhibitor or a nitric oxide inhibitor, blocked V642I-AβPP-induced cytotoxicity. Among mitogen-activated protein kinase (MAPK) family proteins, c-Jun N-terminal kinase (JNK) and p38MAPK, but not extracellular regulated kinase (ERK), were involved in this cytotoxic pathway. The V642I-AβPP-induced cytotoxicity was not suppressed by two secretase inhibitors, suggesting that Aβ does not play a major role in this cytotoxicity. Two neuroprotective factors, insulin-like growth factor I (IGF-I) and Humanin, protected these primary neurons from V642I-AβPP-induced cytotoxicity. Furthermore, interleukin-6 and -11 also attenuated this cytotoxicity. This study demonstrated that the signaling pathway activated by mutated AβPP in the primary neurons is the same as that by the other artificial insults such as antibody binding to AβPP and the artificial dimerization of cytoplasmic domain of AβPP. The potential of neurotrophic factors and cytokines in AD therapy is also indicated.
https://doi.org/10.1002/jnr.20139
c-Jun N-terminal kinase
10.1002/jnr.20139
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Amyloid beta-Protein Precursor Medicine & Life Sciences
Alzheimer Disease Medicine & Life Sciences
Amyloid Medicine & Life Sciences
humanin Medicine & Life Sciences
S-ethyl glutathione Medicine & Life Sciences
Gi-Go GTP-Binding Protein alpha Subunits Medicine & Life Sciences
Protein Multimerization Medicine & Life Sciences
Niikura, T., Yamada, M., Chiba, T., Aiso, S., Matsuoka, M., & Nishimoto, I. (2004). Characterization of V642I-AβPP-induced cytotoxicity in primary neurons. Journal of Neuroscience Research, 77(1), 54-62. https://doi.org/10.1002/jnr.20139
Characterization of V642I-AβPP-induced cytotoxicity in primary neurons. / Niikura, Takako; Yamada, Marina; Chiba, Tomohiro; Aiso, Sadakazu; Matsuoka, Masaaki; Nishimoto, Ikuo.
In: Journal of Neuroscience Research, Vol. 77, No. 1, 01.07.2004, p. 54-62.
Niikura, T, Yamada, M, Chiba, T, Aiso, S, Matsuoka, M & Nishimoto, I 2004, 'Characterization of V642I-AβPP-induced cytotoxicity in primary neurons', Journal of Neuroscience Research, vol. 77, no. 1, pp. 54-62. https://doi.org/10.1002/jnr.20139
Niikura T, Yamada M, Chiba T, Aiso S, Matsuoka M, Nishimoto I. Characterization of V642I-AβPP-induced cytotoxicity in primary neurons. Journal of Neuroscience Research. 2004 Jul 1;77(1):54-62. https://doi.org/10.1002/jnr.20139
Niikura, Takako ; Yamada, Marina ; Chiba, Tomohiro ; Aiso, Sadakazu ; Matsuoka, Masaaki ; Nishimoto, Ikuo. / Characterization of V642I-AβPP-induced cytotoxicity in primary neurons. In: Journal of Neuroscience Research. 2004 ; Vol. 77, No. 1. pp. 54-62.
@article{525f984201bb48b1bf9e159aa1592158,
title = "Characterization of V642I-AβPP-induced cytotoxicity in primary neurons",
abstract = "Amyloid precursor protein (AβPP), a precursor of amyloid β (Aβ) peptide, is one of the molecules involved in the pathogenesis of Alzheimer's disease (AD). Specific mutations in AβPP have been found in patients inheriting familial AD (FAD). These mutant AβPP proteins cause cell death in neuronal cell lines in vitro, but the molecular mechanism of cytotoxicity has not yet been clarified completely. We analyzed the cytotoxic mechanisms of the London-type AβPP mutant, V642I-AβPP, in primary cortical neurons utilizing an adenovirus-mediated gene transfer system. Expression of V642I-AβPP protein induced degeneration of the primary neurons. This cytotoxicity was blocked by pertussis toxin, a specific inhibitor for heterotrimeric G proteins, Go/i, and was suppressed by an inhibitor of caspase-3/7 and an antioxidant, glutathione ethyl ester. A specific inhibitor for NADPH oxidase, apocynin, but not a xanthine oxidase inhibitor or a nitric oxide inhibitor, blocked V642I-AβPP-induced cytotoxicity. Among mitogen-activated protein kinase (MAPK) family proteins, c-Jun N-terminal kinase (JNK) and p38MAPK, but not extracellular regulated kinase (ERK), were involved in this cytotoxic pathway. The V642I-AβPP-induced cytotoxicity was not suppressed by two secretase inhibitors, suggesting that Aβ does not play a major role in this cytotoxicity. Two neuroprotective factors, insulin-like growth factor I (IGF-I) and Humanin, protected these primary neurons from V642I-AβPP-induced cytotoxicity. Furthermore, interleukin-6 and -11 also attenuated this cytotoxicity. This study demonstrated that the signaling pathway activated by mutated AβPP in the primary neurons is the same as that by the other artificial insults such as antibody binding to AβPP and the artificial dimerization of cytoplasmic domain of AβPP. The potential of neurotrophic factors and cytokines in AD therapy is also indicated.",
keywords = "Alzheimer's disease, Humanin, NADPH oxidase, Neurodegeneration, c-Jun N-terminal kinase",
author = "Takako Niikura and Marina Yamada and Tomohiro Chiba and Sadakazu Aiso and Masaaki Matsuoka and Ikuo Nishimoto",
doi = "10.1002/jnr.20139",
journal = "Journal of Neuroscience Research",
T1 - Characterization of V642I-AβPP-induced cytotoxicity in primary neurons
AU - Niikura, Takako
AU - Yamada, Marina
AU - Chiba, Tomohiro
AU - Aiso, Sadakazu
AU - Matsuoka, Masaaki
AU - Nishimoto, Ikuo
N2 - Amyloid precursor protein (AβPP), a precursor of amyloid β (Aβ) peptide, is one of the molecules involved in the pathogenesis of Alzheimer's disease (AD). Specific mutations in AβPP have been found in patients inheriting familial AD (FAD). These mutant AβPP proteins cause cell death in neuronal cell lines in vitro, but the molecular mechanism of cytotoxicity has not yet been clarified completely. We analyzed the cytotoxic mechanisms of the London-type AβPP mutant, V642I-AβPP, in primary cortical neurons utilizing an adenovirus-mediated gene transfer system. Expression of V642I-AβPP protein induced degeneration of the primary neurons. This cytotoxicity was blocked by pertussis toxin, a specific inhibitor for heterotrimeric G proteins, Go/i, and was suppressed by an inhibitor of caspase-3/7 and an antioxidant, glutathione ethyl ester. A specific inhibitor for NADPH oxidase, apocynin, but not a xanthine oxidase inhibitor or a nitric oxide inhibitor, blocked V642I-AβPP-induced cytotoxicity. Among mitogen-activated protein kinase (MAPK) family proteins, c-Jun N-terminal kinase (JNK) and p38MAPK, but not extracellular regulated kinase (ERK), were involved in this cytotoxic pathway. The V642I-AβPP-induced cytotoxicity was not suppressed by two secretase inhibitors, suggesting that Aβ does not play a major role in this cytotoxicity. Two neuroprotective factors, insulin-like growth factor I (IGF-I) and Humanin, protected these primary neurons from V642I-AβPP-induced cytotoxicity. Furthermore, interleukin-6 and -11 also attenuated this cytotoxicity. This study demonstrated that the signaling pathway activated by mutated AβPP in the primary neurons is the same as that by the other artificial insults such as antibody binding to AβPP and the artificial dimerization of cytoplasmic domain of AβPP. The potential of neurotrophic factors and cytokines in AD therapy is also indicated.
AB - Amyloid precursor protein (AβPP), a precursor of amyloid β (Aβ) peptide, is one of the molecules involved in the pathogenesis of Alzheimer's disease (AD). Specific mutations in AβPP have been found in patients inheriting familial AD (FAD). These mutant AβPP proteins cause cell death in neuronal cell lines in vitro, but the molecular mechanism of cytotoxicity has not yet been clarified completely. We analyzed the cytotoxic mechanisms of the London-type AβPP mutant, V642I-AβPP, in primary cortical neurons utilizing an adenovirus-mediated gene transfer system. Expression of V642I-AβPP protein induced degeneration of the primary neurons. This cytotoxicity was blocked by pertussis toxin, a specific inhibitor for heterotrimeric G proteins, Go/i, and was suppressed by an inhibitor of caspase-3/7 and an antioxidant, glutathione ethyl ester. A specific inhibitor for NADPH oxidase, apocynin, but not a xanthine oxidase inhibitor or a nitric oxide inhibitor, blocked V642I-AβPP-induced cytotoxicity. Among mitogen-activated protein kinase (MAPK) family proteins, c-Jun N-terminal kinase (JNK) and p38MAPK, but not extracellular regulated kinase (ERK), were involved in this cytotoxic pathway. The V642I-AβPP-induced cytotoxicity was not suppressed by two secretase inhibitors, suggesting that Aβ does not play a major role in this cytotoxicity. Two neuroprotective factors, insulin-like growth factor I (IGF-I) and Humanin, protected these primary neurons from V642I-AβPP-induced cytotoxicity. Furthermore, interleukin-6 and -11 also attenuated this cytotoxicity. This study demonstrated that the signaling pathway activated by mutated AβPP in the primary neurons is the same as that by the other artificial insults such as antibody binding to AβPP and the artificial dimerization of cytoplasmic domain of AβPP. The potential of neurotrophic factors and cytokines in AD therapy is also indicated.
KW - Alzheimer's disease
KW - Humanin
KW - NADPH oxidase
KW - c-Jun N-terminal kinase
U2 - 10.1002/jnr.20139
DO - 10.1002/jnr.20139
JO - Journal of Neuroscience Research
JF - Journal of Neuroscience Research