Amyloid precursor protein-processing products affect mononuclear phagocyte activation: pathways for sAPP- and Abeta-mediated neurotoxicity.
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 beta-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 beta-peptide (Abeta) 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 Abeta 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.
Ikezu
Tsuneya
T
Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE 68198-5215, USA. tikezu@unmc.edu
Luo
Xiaoguang
X
Weber
Gregory A
GA
Zhao
Jianxing
J
McCabe
Laura
L
Buescher
James L
JL
Ghorpade
Anuja
A
Zheng
Jialin
J
Xiong
Huangui
H
D027182:Amino Acid Transport System y+; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000633:toxicity*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D016166:Free Radical Scavengers / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D016716:PC12 Cells; D018408:Patch-Clamp Techniques; D010586:Phagocytes / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D011499:Protein Processing, Post-Translational; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014162:Transfection; D014982:Xenopus laevis
D027182:Amino Acid Transport System y+; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins; D016166:Free Radical Scavengers; C118895:SLC7A11 protein, human; D018698:Glutamic Acid; D007770:L-Lactate Dehydrogenase