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 β-amyloid (Aβ) and neurofibrillary tangles composed of hyperphosphorylated tau. Recent evidence indicates that in AD altered Zn2+ homeostasis can play an important role in the development of the disease as the cation promotes Aβ oligomerization and plaque formation. In this study, we investigated whether intraneuronal Zn2+ 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 Zn2+ ([Zn2+]i) and we therefore evaluated ROS-driven [Zn2+]i rises in neurons obtained from triple transgenic AD mice (3xTg-AD) that express mutant APP, PS1 and tau. In this study, [Zn2+]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 Zn2+ homeostasis.