The role of an astrocytic NADPH oxidase in the neurotoxicity of amyloid beta peptides

被引:133
作者
Abramov, AY [1 ]
Duchen, MR [1 ]
机构
[1] UCL, Dept Physiol, London WC1E 6BT, England
基金
英国惠康基金;
关键词
amyloid; Alzheimer; NADPH oxidase; intracellular calcium; glutathione;
D O I
10.1098/rstb.2005.1766
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
Amyloid beta peptide (A beta) accumulates in the CNS in Alzheimer's disease. Both the full peptide (1-42) or the 25-35 fragment are toxic to neurons in culture. We have used fluorescence imaging technology to explore the mechanism of neurotoxicity in mixed asytrocyte/neuronal cultures prepared from rat or mouse cortex or hippocampus, and have found that A beta acts preferentially on astrocytes but causes neuronal death. A beta causes sporadic transient increases in [Ca2+](c) in astrocytes, associated with a calcium dependent increased generation of reactive oxygen species (ROS) and glutathione depletion. This caused a slow dissipation of mitochondrial potential on which abrupt calcium dependent transient depolarizations were superimposed. The mitochondrial. depolarization was reversed by mitochondrial substrates glutamate, pyruvate or methyl succinate, and by NADPH oxidase (NOX) inhibitors, suggesting that it reflects oxidative damage to metabolic pathways upstream of mitochondrial complex I. The AD induced increase in ROS and the mitochondrial depolarization were absent in cells cultured from transgenic mice lacking the NOX component, gp91(phox). Neuronal death after 24 h of A beta exposure was dramatically reduced both by NOX inhibitors and in gp91(phox) knockout mice. Thus, by raising [Ca2+](c) in astrocytes, AD activates NOX, generating oxidative stress that is transmitted to neurons, causing neuronal death.
引用
收藏
页码:2309 / 2314
页数:6
相关论文
共 25 条
[1]   Expression and modulation of an NADPH oxidase in mammalian astrocytes [J].
Abramov, AY ;
Jacobson, J ;
Wientjes, F ;
Hothersall, J ;
Canevari, L ;
Duchen, MR .
JOURNAL OF NEUROSCIENCE, 2005, 25 (40) :9176-9184
[2]   Calcium signals induced by amylold β peptide and their consequences in neurons and astrocytes in culture [J].
Abramov, AY ;
Canevari, L ;
Duchen, MR .
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, 2004, 1742 (1-3) :81-87
[3]  
Abramov AY, 2003, J NEUROSCI, V23, P5088
[4]   GIANT MULTILEVEL CATION CHANNELS FORMED BY ALZHEIMER-DISEASE AMYLOID BETA-PROTEIN [A-BETA-P-(1-40)] IN BILAYER-MEMBRANES [J].
ARISPE, N ;
POLLARD, HB ;
ROJAS, E .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (22) :10573-10577
[5]   Plasma membrane cholesterol controls the cytotoxicity of Alzheimer's disease AβP (1-40) and (1-42) peptides [J].
Arispe, N ;
Doh, M .
FASEB JOURNAL, 2002, 16 (12) :1526-1536
[6]   Zn2+ interaction with Alzheimer amyloid beta protein calcium channels [J].
Arispe, N ;
Pollard, HB ;
Rojas, E .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1996, 93 (04) :1710-1715
[7]   Fresh and globular amyloid β protein (1-42) induces rapid cellular degeneration:: evidence for AβP channel-mediated cellular toxicity [J].
Bhatia, R ;
Lin, H ;
Lal, R .
FASEB JOURNAL, 2000, 14 (09) :1233-1243
[8]  
BLASS JP, 1991, REV NEUROL, V147, P513
[9]   The metallobiology of Alzheimer's disease [J].
Bush, AI .
TRENDS IN NEUROSCIENCES, 2003, 26 (04) :207-214
[10]   Toxicity of amyloid β peptide:: Tales of calcium, mitochondria, and oxidative stress [J].
Canevari, L ;
Abramov, AY ;
Duchen, MR .
NEUROCHEMICAL RESEARCH, 2004, 29 (03) :637-650