A key role for the microglial NADPH oxidase in APP-dependent killing of neurons.
Reactive oxygen species (ROS) and deposition of cleaved products of amyloid precursor protein (APP) are thought to contribute to neuronal loss observed in Alzheimer's disease (AD). The relationship between these factors was studied in a neuroblastoma and microglia co-culture system. Overexpression of wild-type APP (APP-wt) or APP with three mutations typical of familial AD (APP-3m) in SH-SY5Y neuroblastoma cells did not directly alter their morphology, growth rate, cell cycle or H(2)O(2) sensitivity. In a co-culture of APP-wt neuroblastoma cells with microglia, microglial cells generated ROS and neuronal cells died. The cell death was more pronounced in APP-3m-expressing neurons. Neuroblastoma cell death was attenuated by ROS-scavengers and was dose-dependently inhibited by the NADPH oxidase inhibitor diphenyleneiodonium chloride (DPI). Macrophage cell lines behaved similarly to microglia in the co-culture model. However, a macrophage cell line deficient in the NADPH oxidase subunit, gp91phox, failed to kill neurons. These results suggest that APP-dependent microglia activation and subsequent ROS generation by the phagocyte NADPH oxidase play a crucial role in neuronal killing in a cellular model of AD.
Qin
Bin
B
Biology of Ageing Laboratory, Department of Geriatrics, Geneva University Hospitals, 2 chemin Petit Bel-Air, 1225 Chêne-Bourg, Geneva, Switzerland.
Cartier
Laetitia
L
Dubois-Dauphin
Michel
M
Li
Bin
B
Serrander
Lena
L
Krause
Karl-Heinz
KH
D000544:Alzheimer Disease / Q000503:physiopathology*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000975:Antioxidants / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology; D015153:Blotting, Western; D002452:Cell Count; D018929:Cell Culture Techniques; D016923:Cell Death; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009154:Mutation; D019255:NADPH Oxidases / Q000172:deficiency / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009861:Onium Compounds / Q000494:pharmacology; D058255:Protease Nexins; D017382:Reactive Oxygen Species / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D014161:Transduction, Genetic; D014810:Vitamin E / Q000494:pharmacology
C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D000975:Antioxidants; D004791:Enzyme Inhibitors; D009861:Onium Compounds; D058255:Protease Nexins; D017382:Reactive Oxygen Species; D011956:Receptors, Cell Surface; D014810:Vitamin E; C007517:diphenyleneiodonium; D019255:NADPH Oxidases; D001205:Ascorbic Acid