Divalent metal transporter 1 is involved in amyloid precursor protein processing and Aβ generation

The amyloid-β precursor protein (APP) and its pathogenic byproduct β-amyloid peptide (Aβ) play central roles in the pathogenesis of Alzheimer's disease (AD). Reduction in levels of the potentially toxic Aβ is one of the most important therapeutic goals in AD. Recent studies have shown that bivalent metals such as iron, copper, and zinc are involved in APP expression, Aβ deposition, and senile plaque formation in the AD brain. However, the underlying mechanisms involved in abnormal homeostasis of bivalent metals in AD brain remain unclear. In the present study, we found that two isoforms of the divalent metal transporter 1 (DMT1), DMT1-IRE, and DMTl-nonIRE, were colocalized with Aβ in the plaques of postmortem AD brain. Using the APP/PS1 transgenic mouse model, we found that the levels of both DMT1-IRE and DMT1-nonlRE were significantly increased in the cortex and hippocampus compared with wild type-control. We further verified the proposed mechanisms by which DMT1 might be involved in APP processing and Aβ secretion by using the SH-SY5Y cell line stably overex-pressing human APP Swedish mutation (APPsw) as a cell model. We found that overexpression of APPsw resulted in increased expression levels of both DMT1-IRE and DMTl-nonIRE in SH-SY5Y cells. Interestingly, silencing of endogenous DMT1 by RNA interference, which reduced bivalent ion influx, led to reductions of APP expression and Aß secretion. These findings suggest both that DMT1 plays a critical role in ion-mediated neuropathogenesis in AD and that pharmacological blockage of DMT1 may provide novel therapeutic strategies against AD.—Zheng, W., Xin, N., Chi, Z.-H., Zhao, B.-L., Zhang, J., Li, J.-Y., Wang, Z.-Y. Divalent metal transporter 1 (DMT1) is involved in amyloid precursor protein processing and Aß generation. FASEBJ. 23, 4207-4217 (2009). www.fasebj.org