Characterization of V642I-AβPP-induced cytotoxicity in primary neurons

Takako Niikura, Marina Yamada, Tomohiro Chiba, Sadakazu Aiso, Masaaki Matsuoka, Ikuo Nishimoto

Research output: Contribution to journalArticle

40 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)54-62
Number of pages9
JournalJournal of Neuroscience Research
Volume77
Issue number1
DOIs
Publication statusPublished - 2004 Jul 1

Fingerprint

Amyloid beta-Protein Precursor
Neurons
Alzheimer Disease
Amyloid
Protein Multimerization
Gi-Go GTP-Binding Protein alpha Subunits
Interleukin-11
Caspase 7
Serum Amyloid A Protein
Heterotrimeric GTP-Binding Proteins
Nerve Degeneration
Amyloid Precursor Protein Secretases
Proteins
JNK Mitogen-Activated Protein Kinases
Xanthine Oxidase
NADPH Oxidase
Pertussis Toxin
Nerve Growth Factors
Mutant Proteins
Mitogen-Activated Protein Kinases

Keywords

  • Alzheimer's disease
  • c-Jun N-terminal kinase
  • Humanin
  • NADPH oxidase
  • Neurodegeneration

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

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.

Research output: Contribution to journalArticle

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.
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