Amyloid precursor protein-processing products affect mononuclear phagocyte activation: Pathways for sAPP- and Aβ-mediated neurotoxicity

Tsuneya Ikezu, Xiaoguang Luo, Gregory A. Weber, Jianxing Zhao, Laura McCabe, James L. Buescher, Anuja Ghorpade, Jialin C Zheng, Huangui Xiong

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Increasing evidence strongly supports the role of glial immunity in the pathogenesis of Alzheimer's disease (AD). To investigate such events we have developed cell systems mimicking the interactions between β-amyloid precursor protein (APP)-expressing neurons and brain mononuclear phagocytes (MP; macrophages and microglia). MP were co-cultured with neuronal cells expressing wild type APP or familial AD-linked APP mutants. The latter was derived from recombinant adenoviral constructs. Neuronal APP processing products induced MP activation, reactive oxygen species, and neurotoxic activities. These occurred without the addition of pro-inflammatory cytokines and were reversed by depletion of amyloid β-peptide (Aβ) and secreted APP (sAPP). Neurotoxic activities were diminished by superoxide dismutase mimetics and NMDA receptor inhibitors. Microglial glutamate secretion was suppressed by the cystine-glutamate antiporter inhibitor and its levels paralleled the depletion of sAPP and Aβ from conditioned media prepared from APP-expressing neurons. The excitotoxins from activated MP were potent enough to evoke recombinant NMDA receptor-mediated inward currents expressed in vitro in the Xenopus oocytes. These results demonstrate that neuronal APP-processing products can induce oxidative neurotoxicity through microglial activation.

Original languageEnglish (US)
Pages (from-to)925-934
Number of pages10
JournalJournal of Neurochemistry
Volume85
Issue number4
DOIs
StatePublished - May 2003

Fingerprint

Amyloid beta-Protein Precursor
Phagocytes
Chemical activation
Processing
N-Methyl-D-Aspartate Receptors
Neurons
Glutamic Acid
Alzheimer Disease
Antiporters
Cystine
Macrophages
Neurotoxins
Microglia
Conditioned Culture Medium
Xenopus
Amyloid
Neuroglia
Superoxide Dismutase
Oocytes
Immunity

Keywords

  • Alzheimer's disease
  • Amyloid precursor protein
  • Glutamate
  • Microglia
  • Neurotoxicity

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Amyloid precursor protein-processing products affect mononuclear phagocyte activation : Pathways for sAPP- and Aβ-mediated neurotoxicity. / Ikezu, Tsuneya; Luo, Xiaoguang; Weber, Gregory A.; Zhao, Jianxing; McCabe, Laura; Buescher, James L.; Ghorpade, Anuja; Zheng, Jialin C; Xiong, Huangui.

In: Journal of Neurochemistry, Vol. 85, No. 4, 05.2003, p. 925-934.

Research output: Contribution to journalArticle

Ikezu, Tsuneya ; Luo, Xiaoguang ; Weber, Gregory A. ; Zhao, Jianxing ; McCabe, Laura ; Buescher, James L. ; Ghorpade, Anuja ; Zheng, Jialin C ; Xiong, Huangui. / Amyloid precursor protein-processing products affect mononuclear phagocyte activation : Pathways for sAPP- and Aβ-mediated neurotoxicity. In: Journal of Neurochemistry. 2003 ; Vol. 85, No. 4. pp. 925-934.
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