 |
The Journal of Neuroscience, January 14, 2004, 24(2):565-575; doi:10.1523/JNEUROSCI.4042-03.2004
 Previous Article | Next Article 
Neurobiology of Disease
 -Amyloid Peptides Induce Mitochondrial Dysfunction and Oxidative Stress in Astrocytes and Death of Neurons through Activation of NADPH Oxidase
Andrey Y. Abramov,1
Laura Canevari,2 and
Michael R. Duchen1
1Mitochondrial Biology Group, Department of Physiology, University College London, London WC1E 6BT, United Kingdom, and 2Division of Neurochemistry, Institute of Neurology, London WC1N 3BG, United Kingdom
 -Amyloid (A) peptide is strongly implicated in the neurodegeneration underlying Alzheimer's disease, but the mechanisms of neurotoxicity remain controversial. This study establishes a central role for oxidative stress by the activation of NADPH oxidase in astrocytes as the cause of A-induced neuronal death. A causes a loss of mitochondrial potential in astrocytes but not in neurons. The mitochondrial response consists of Ca2+-dependent transient depolarizations superimposed on a slow collapse of potential. The slow response is both prevented by antioxidants and, remarkably, reversed by provision of glutamate and other mitochondrial substrates to complexes I and II. These findings suggest that the depolarization reflects oxidative damage to metabolic pathways upstream of mitochondrial respiration. Inhibition of NADPH oxidase by diphenylene iodonium or 4-hydroxy-3-methoxy-acetophenone blocks A-induced reactive oxygen species generation, prevents the mitochondrial depolarization, prevents A-induced glutathione depletion in both neurons and astrocytes, and protects neurons from cell death, placing the astrocyte NADPH oxidase as a primary target of A-induced neurodegeneration.
Key words: Alzheimer; astrocyte; astroglia; calcium; mitochondria; NADPH; neuron
Received Sep 2, 2003;
revised November 13, 2003;
accepted November 14, 2003.
This article has been cited by other articles:
|
|
|
|
 
M. Ibi, K. Matsuno, D. Shiba, M. Katsuyama, K. Iwata, T. Kakehi, T. Nakagawa, K. Sango, Y. Shirai, T. Yokoyama, et al.
Reactive Oxygen Species Derived from NOX1/NADPH Oxidase Enhance Inflammatory Pain
J. Neurosci.,
September 17, 2008;
28(38):
9486 - 9494.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Sharma, N. Singh, and M. Singh
Modulation of celecoxib- and streptozotocin-induced experimental dementia of Alzheimer's disease by pitavastatin and donepezil
J Psychopharmacol,
March 1, 2008;
22(2):
162 - 171.
[Abstract]
[PDF]
|
|
|
|
|
|
|
H. K. Anandatheerthavarada and L. Devi
Amyloid Precursor Protein and Mitochondrial Dysfunction in Alzheimer's Disease
Neuroscientist,
December 1, 2007;
13(6):
626 - 638.
[Abstract]
[PDF]
|
|
|
|
|
|
|
A. Y. Abramov, C. Fraley, C. T. Diao, R. Winkfein, M. A. Colicos, M. R. Duchen, R. J. French, and E. Pavlov
Targeted polyphosphatase expression alters mitochondrial metabolism and inhibits calcium-dependent cell death
PNAS,
November 13, 2007;
104(46):
18091 - 18096.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Shan, Y. Chang, and C.-l. G. Lin
Messenger RNA oxidation is an early event preceding cell death and causes reduced protein expression
FASEB J,
September 1, 2007;
21(11):
2753 - 2764.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Y. Abramov, A. Scorziello, and M. R. Duchen
Three Distinct Mechanisms Generate Oxygen Free Radicals in Neurons and Contribute to Cell Death during Anoxia and Reoxygenation
J. Neurosci.,
January 31, 2007;
27(5):
1129 - 1138.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Zhu, Y. Lai, P. B. Shelat, C. Hu, G. Y. Sun, and J. C-M. Lee
Phospholipases A2 Mediate Amyloid-beta Peptide-Induced Mitochondrial Dysfunction
J. Neurosci.,
October 25, 2006;
26(43):
11111 - 11119.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Rui, P. Tiwari, Z. Xie, and J. Q. Zheng
Acute Impairment of Mitochondrial Trafficking by beta-Amyloid Peptides in Hippocampal Neurons
J. Neurosci.,
October 11, 2006;
26(41):
10480 - 10487.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Livigni, A. Scorziello, S. Agnese, A. Adornetto, A. Carlucci, C. Garbi, I. Castaldo, L. Annunziato, E. V. Avvedimento, and A. Feliciello
Mitochondrial AKAP121 Links cAMP and src Signaling to Oxidative Metabolism
Mol. Biol. Cell,
January 1, 2006;
17(1):
263 - 271.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Santos, R. A. Quintanilla, A. Toro, R. Grandy, M. C. Dinamarca, J. A. Godoy, and N. C. Inestrosa
Peroxisomal Proliferation Protects from {beta}-Amyloid Neurodegeneration
J. Biol. Chem.,
December 9, 2005;
280(49):
41057 - 41068.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Y. Abramov, J. Jacobson, F. Wientjes, J. Hothersall, L. Canevari, and M. R. Duchen
Expression and Modulation of an NADPH Oxidase in Mammalian Astrocytes
J. Neurosci.,
October 5, 2005;
25(40):
9176 - 9184.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Zhan, F. Serrano, P. Fenik, R. Hsu, L. Kong, D. Pratico, E. Klann, and S. C. Veasey
NADPH Oxidase Mediates Hypersomnolence and Brain Oxidative Injury in a Murine Model of Sleep Apnea
Am. J. Respir. Crit. Care Med.,
October 1, 2005;
172(7):
921 - 929.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Hirata, H. Yamaguchi, Y. Takamura, A. Takagi, T. Fukushima, N. Iwakami, A. Saitoh, M. Nakagawa, and T. Yamada
A Novel Neurotrophic Agent, T-817MA [1-{3-[2-(1-Benzothiophen-5-yl) Ethoxy] Propyl}-3-azetidinol Maleate], Attenuates Amyloid-{beta}-Induced Neurotoxicity and Promotes Neurite Outgrowth in Rat Cultured Central Nervous System Neurons
J. Pharmacol. Exp. Ther.,
July 1, 2005;
314(1):
252 - 259.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. T. Brown, J. L. Scragg, J. P. Boyle, K. Hudasek, C. Peers, and I. M. Fearon
Hypoxic Augmentation of Ca2+ Channel Currents Requires a Functional Electron Transport Chain
J. Biol. Chem.,
June 10, 2005;
280(23):
21706 - 21712.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Di Lisa and P. Bernardi
Mitochondrial function and myocardial aging. A critical analysis of the role of permeability transition
Cardiovasc Res,
May 1, 2005;
66(2):
222 - 232.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S.-H. Choi, D. Y. Lee, S. U. Kim, and B. K. Jin
Thrombin-Induced Oxidative Stress Contributes to the Death of Hippocampal Neurons In Vivo: Role of Microglial NADPH Oxidase
J. Neurosci.,
April 20, 2005;
25(16):
4082 - 4090.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. K. Aley, K. E. Porter, J. P. Boyle, P. J. Kemp, and C. Peers
Hypoxic Modulation of Ca2+ Signaling in Human Venous Endothelial Cells: MULTIPLE ROLES FOR REACTIVE OXYGEN SPECIES
J. Biol. Chem.,
April 8, 2005;
280(14):
13349 - 13354.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Park, J. Anrather, P. Zhou, K. Frys, R. Pitstick, S. Younkin, G. A. Carlson, and C. Iadecola
NADPH Oxidase-Derived Reactive Oxygen Species Mediate the Cerebrovascular Dysfunction Induced by the Amyloid {beta} Peptide
J. Neurosci.,
February 16, 2005;
25(7):
1769 - 1777.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. T. Brown, R. P. Johnson, R. Senaratne, and I. M. Fearon
Amyloid {beta} peptides mediate physiological remodelling of the acute O2 sensitivity of adrenomedullary chromaffin cells following chronic hypoxia
Cardiovasc Res,
December 1, 2004;
64(3):
536 - 543.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. K. Young and J. C. McKenzie
GLUT2 Immunoreactivity in Gomori-positive Astrocytes of the Hypothalamus
J. Histochem. Cytochem.,
November 1, 2004;
52(11):
1519 - 1524.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
