Abramov, AY and Duchen, MR (2005) The role of an astrocytic NADPH oxidase in the neurotoxicity of amyloid beta peptides. PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES , 360 (1464) 2309 - 2314. 10.1098/rstb.2005.1766.
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.
|Title:||The role of an astrocytic NADPH oxidase in the neurotoxicity of amyloid beta peptides|
|Open access status:||An open access publication|
|Publisher version:||http://www.ncbi.nlm.nih.gov/pmc/ articles/PMC1569597/?tool=pubmed|
|Keywords:||amyloid, Alzheimer, NADPH oxidase, intracellular calcium, glutathione, ALZHEIMERS-DISEASE, INTRACELLULAR CALCIUM, PROTEIN, GLUTATHIONE, CHANNELS, NEURONS, PATHOPHYSIOLOGY, CHOLESTEROL, TOXICITY, CULTURE|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Neurology > Molecular Neuroscience|
UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of) > Cell and Developmental Biology
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