Abstract
BackgroundAbnormal zinc homeostasis is involved in β-amyloid (Aβ) plaque formation and, therefore, the zinc load is a contributing factor in Alzheimer's disease (AD). However, the involvement of zinc in amyloid precursor protein (APP) processing and Aβ deposition has not been well established in AD animal models in vivo.Methodology/Principal FindingsIn the present study, APP and presenilin 1 (PS1) double transgenic mice were treated with a high dose of zinc (20 mg/ml ZnSO4 in drinking water). This zinc treatment increased APP expression, enhanced amyloidogenic APP cleavage and Aβ deposition, and impaired spatial learning and memory in the transgenic mice. We further examined the effects of zinc overload on APP processing in SHSY-5Y cells overexpressing human APPsw. The zinc enhancement of APP expression and cleavage was further confirmed in vitro.Conclusions/SignificanceThe present data indicate that excess zinc exposure could be a risk factor for AD pathological processes, and alteration of zinc homeostasis is a potential strategy for the prevention and treatment of AD.
Highlights
The presence of extracellular b-amyloid (Ab) plaques in the brain is one of the pathological hallmarks of Alzheimer’s disease (AD)
We have reported that high levels of ZnT1, 3-7 and divalent metal transporter 1 (DMT1) proteins are located in the degenerating neurites in or around the Ab-positive plaques associated with human AD and the amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse brain [18,19,20,21]
The probe trial showed that the number of times the mice traveled into the center of the northwest quadrant, where the hidden platform was previously placed, was significantly less for zinc group mice compared with controls (p,0.01; Figure 1C)
Summary
The presence of extracellular b-amyloid (Ab) plaques in the brain is one of the pathological hallmarks of Alzheimer’s disease (AD). Since Ab peptide has zinc-binding sites, and zinc is the only physiologically available metal able to precipitate Ab, the abnormal enrichment of zinc in the AD brain indicates that zinc binding to Ab plays a role in the formation of amyloid plaques [11]. Zinc chelating agents, such as clioquinol (CQ) and DP-109, that modulate brain zinc levels can inhibit the formation of amyloid plaques [12,13,14]. Abnormal zinc homeostasis is involved in b-amyloid (Ab) plaque formation and, the zinc load is a contributing factor in Alzheimer’s disease (AD). The involvement of zinc in amyloid precursor protein (APP) processing and Ab deposition has not been well established in AD animal models in vivo
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