Brain iron deposition and the free radical-mitochondrial theory of ageing.
The central hypothesis of this paper states that oxidative stress, augmented iron deposition, and mitochondrial insufficiency in the ageing and degenerating CNS constitute a single neuropathological 'lesion', and that the advent of one component of this triad obligates the appearance of the others. Evidence in support of this unifying perspective is adduced from human neuropathological studies, experimental paradigms of ageing-associated neurological disorders, and a comprehensive model of astroglial senescence. A pivotal role for the enzyme, heme oxygenase-1 (HO-1) in consolidating this tripartite lesion in the ageing and diseased CNS is emphasized. The data are discussed in the context of a revised 'free radical-mitochondrial-metal' theory of brain ageing, and some scientific and clinical implications of the latter are considered.
Schipper
Hyman M
HM
Centre for Neurotranslational Research and Bloomfield Centre for Research in Ageing, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, Que., Canada. hyman@schipper@mcgill.ca
D000375:Aging; D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002396:Catechols / Q000378:metabolism / Q000494:pharmacology; D002493:Central Nervous System Diseases / Q000378:metabolism / Q000503:physiopathology; D003543:Cysteamine / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008565:Membrane Proteins; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008954:Models, Biological; D018384:Oxidative Stress / Q000502:physiology; D010300:Parkinson Disease / Q000378:metabolism / Q000503:physiopathology; D009195:Peroxidase / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism
D002396:Catechols; D005609:Free Radicals; D008565:Membrane Proteins; D003543:Cysteamine; D007501:Iron; D009195:Peroxidase; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D013482:Superoxide Dismutase