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

• Published in: Journal of neurochemistry Vol. 85; no. 4; pp. 925 - 934
• Main Authors: Ikezu, Tsuneya, Luo, Xiaoguang, Weber, Gregory A., Zhao, Jianxing, McCabe, Laura, Buescher, James L., Ghorpade, Anuja, Zheng, Jialin, Xiong, Huangui
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.05.2003; Blackwell
• Subjects: Alzheimer's disease; amyloid precursor protein; Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; glutamate; Medical sciences; microglia; Neurology; neurotoxicity; Rat; Alzheimer disease; Pathogenesis; Neuroglia; Mononuclear cell; neurotoxicity; Degenerative disease; Oxidation; Glycine dehydrogenase (decarboxylating); Alzheimer's disease; Nervous system diseases; Enzyme; Rodentia; Glutamate; Amyloid precursor protein; Cerebral disorder; Microglia; Toxin; Vertebrata; Mammalia; β Amyloid protein; Animal; Central nervous system disease; Neurotoxin; Excitatory aminoacid; Neurotransmitter; Oxidoreductases; NMDA receptor; Macrophage; Phagocyte
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.1471-4159.2003.01739.x

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.