Alzheimer's disease (AD) is a neurodegenerative disease characterized by the aggregation of amyloid β-peptide (Aβ) into β-sheet-rich fibrils. Although plaques containing Aβ fibrils have been viewed as the conventional hallmark of AD, recent research implicates small oligomeric species formed during the aggregation of Aβ in the neuronal toxicity and cognitive deficits associated with AD. We have demonstrated that oligomers, but not monomers, of Aβ40 and Aβ42 were found to induce calcium signalling in astrocytes but not in neurons. This cell specificity was dependent on the higher cholesterol level in the membrane of astrocytes compared with neurons. The Aβ-induced calcium signal stimulated NADPH oxidase and induced increased reactive oxygen species (ROS) production. These events are detectable at physiologically relevant concentrations of Aβ. Excessive ROS production and Ca2+ overload induced mitochondrial depolarization through activation of the DNA repairing enzyme poly(ADP-ribose) polymerase-1 (PARP-1) and opening mitochondrial permeability transition pore (mPTP). Aβ significantly reduced the level of GSH in both astrocytes and neurons, an effect which is dependent on external calcium. Thus Aβ induces a [Ca2+]c signal in astrocytes which could regulate the GSH level in co-cultures that in the area of excessive ROS production could be a trigger for neurotoxicity. The pineal hormone melatonin, the glycoprotein clusterin and regulation of the membrane cholesterol can modify Aβ-induced calcium signals, ROS production and mitochondrial depolarization, which eventually lead to neuroprotection.
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October 2014
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Conference Article|
September 18 2014
Interaction of neurons and astrocytes underlies the mechanism of Aβ-induced neurotoxicity
Plamena R. Angelova;
Plamena R. Angelova
*Department of Molecular Neuroscience, Institute of Neurology, UCL, Queen Square, WC1N 3BG, London, U.K.
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Andrey Y. Abramov
Andrey Y. Abramov
1
*Department of Molecular Neuroscience, Institute of Neurology, UCL, Queen Square, WC1N 3BG, London, U.K.
1To whom the correspondence should be addressed (emaila.abramov@ucl.ac.uk).
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Publisher: Portland Press Ltd
Received:
May 28 2014
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2014 Biochemical Society
2014
Biochem Soc Trans (2014) 42 (5): 1286–1290.
Article history
Received:
May 28 2014
Citation
Plamena R. Angelova, Andrey Y. Abramov; Interaction of neurons and astrocytes underlies the mechanism of Aβ-induced neurotoxicity. Biochem Soc Trans 1 October 2014; 42 (5): 1286–1290. doi: https://doi.org/10.1042/BST20140153
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