Metals and amyloid-beta in Alzheimer's disease.
Mounting evidence is demonstrating roles for the amyloid precursor protein (APP) and its proteolytic product Abeta in metal homeostasis. Furthermore, aberrant metal homeostasis is observed in patients with Alzheimer's disease (AD), and this may contribute to AD pathogenesis, by enhancing the formation of reactive oxygen species and toxic Abeta oligomers and facilitating the formation of the hallmark amyloid deposits in AD brain. Indeed, zinc released from synaptic activity has been shown to induce parenchymal and cerebrovascular amyloid in transgenic mice. On the other hand, abnormal metabolism of APP and Abeta may impair brain metal homeostasis as part of the AD pathogenic process. Abeta and APP expression have both been shown to decrease brain copper (Cu) levels, whereas increasing brain Cu availability results in decreased levels of Abeta and amyloid plaque formation in transgenic mice. Lowering Cu concentrations can downregulate the transcription of APP, strengthening the hypothesis that APP and Abeta form part of the Cu homeostatic machinery in the brain. This is a complex pathway, and it appears that when the sensitive metal balance in the brain is sufficiently disrupted, it can lead to the self-perpetuating pathogenesis of AD. Clinical trials are currently studying agents that can remedy abnormal Abeta-metal interactions.
Maynard
Christa J
CJ
Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia.
Bush
Ashley I
AI
Masters
Colin L
CL
Cappai
Roberto
R
Li
Qiao-Xin
QX
D000375:Aging / Q000502:physiology; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D003300:Copper / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D008670:Metals / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000502:physiology; D013569:Synapses / Q000378:metabolism; D015032:Zinc / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008670:Metals; D003300:Copper; D015032:Zinc