Altered oxidant-mediated intraneuronal zinc mobilization in a triple transgenic mouse model of Alzheimer's disease.
Alzheimer's disease (AD) is responsible for the most common form of dementia among elderly people. Signature features of the AD brain are intra/extracellular deposits of beta-amyloid (Abeta) and neurofibrillary tangles composed of hyperphosphorylated tau. Recent evidence indicates that in AD altered Zn(2+) homeostasis can play an important role in the development of the disease as the cation promotes Abeta oligomerization and plaque formation. In this study, we investigated whether intraneuronal Zn(2+) homeostasis is affected by known "pro-AD factors" such as mutant forms of the amyloid precursor (APP), presenilin-1 (PS1), and tau proteins. Oxidative stress is a potent trigger for mobilization of intracellular free Zn(2+) ([Zn(2+)](i)) and we therefore evaluated ROS-driven [Zn(2+)](i) rises in neurons obtained from triple transgenic AD mice (3xTg-AD) that express mutant APP, PS1 and tau. In this study, [Zn(2+)](i) rises triggered by prolonged exposure to the membrane-permeant oxidizing agent 2,2'-dithiodipyridine were found to be significantly higher in 3xTg-AD neurons when compared to control cultures, suggesting that neuronal expression of pro-AD factors can facilitate altered Zn(2+) homeostasis.
Sensi
Stefano L
SL
Department of Basic and Applied Medical Science, CeSI-Center for Excellence on Aging, University G. d'Annunzio, Chieti, 66013, Italy. ssensi@uci.edu
Rapposelli
Ilario G
IG
Frazzini
Valerio
V
Mascetra
Nicola
N
D015082:2,2'-Dipyridyl / Q000031:analogs & derivatives / Q000494:pharmacology; D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004220:Disulfides / Q000494:pharmacology; D006706:Homeostasis / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology; D015032:Zinc / Q000378:metabolism*
D004220:Disulfides; D016877:Oxidants; C001105:2,2'-dipyridyl disulfide; D015082:2,2'-Dipyridyl; D015032:Zinc