Toxicity of amyloid beta peptide: tales of calcium, mitochondria, and oxidative stress.
Alzheimer's disease (AD) is characterized by the accumulation of amyloid-beta (Abeta) peptides. Although the disease undoubtedly reflects the interaction of complex multifactorial processes, Abeta itself is toxic to neurons in vitro and the load of Abeta in vivo correlates well with the degree of cognitive impairment. There has therefore been considerable interest in the mechanism(s) of Abeta neurotoxicity. We here review the basic biology of Abeta processing and consider some of the major areas of focus of this research. It is clear that both AD and Abeta toxicity are characterized by oxidative stress, alterations in the activity of enzymes of intermediary metabolism, and mitochondrial dysfunction, especially impaired activity of cytochrome c oxidase. Studies in vitro also show alterations in cellular calcium signaling. We consider the mechanisms proposed to mediate cell injury and explore evidence to indicate which of these many changes in function are primary and which secondary.
Canevari
Laura
L
Division of Neurochemistry, Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom. L.Canevari@ion.ucl.ac.uk
Abramov
Andrey Y
AY
Duchen
Michael R
MR
D000544:Alzheimer Disease / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002118:Calcium / Q000502:physiology*; D020013:Calcium Signaling / Q000187:drug effects; D002449:Cell Aggregation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects*
D016229:Amyloid beta-Peptides; D005978:Glutathione; D002118:Calcium