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Divalent metal transporter 1 is involved in amyloid precursor protein processing and A{beta} generation.

Zheng, Wei; Xin, Na; Chi, Zhi-Hong; Zhao, Bo-Lu; Zhang, Jie; Li, Jia-Yi LU and Wang, Zhan-You (2009) In FASEB Journal 23(12). p.4207-4217
Abstract
The amyloid-beta precursor protein (APP) and its pathogenic byproduct beta-amyloid peptide (Abeta) play central roles in the pathogenesis of Alzheimer's disease (AD). Reduction in levels of the potentially toxic Abeta 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, Abeta 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 DMT1-nonIRE, were colocalized with Abeta in the plaques of postmortem AD brain.... (More)
The amyloid-beta precursor protein (APP) and its pathogenic byproduct beta-amyloid peptide (Abeta) play central roles in the pathogenesis of Alzheimer's disease (AD). Reduction in levels of the potentially toxic Abeta 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, Abeta 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 DMT1-nonIRE, were colocalized with Abeta 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-nonIRE 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 Abeta secretion by using the SH-SY5Y cell line stably overexpressing 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 DMT1-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 Abeta 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 Abeta generation. (Less)
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organization
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type
Contribution to journal
publication status
published
subject
in
FASEB Journal
volume
23
issue
12
pages
4207 - 4217
publisher
The Federation of American Societies for Experimental Biology
external identifiers
  • wos:000272193700016
  • pmid:19679638
  • scopus:72749101173
ISSN
1530-6860
DOI
10.1096/fj.09-135749
language
English
LU publication?
yes
id
7fd9cef5-d977-455c-9d80-1a8b7b31dfc6 (old id 1469754)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19679638?dopt=Abstract
date added to LUP
2009-09-11 12:13:50
date last changed
2017-11-05 03:37:46
@article{7fd9cef5-d977-455c-9d80-1a8b7b31dfc6,
  abstract     = {The amyloid-beta precursor protein (APP) and its pathogenic byproduct beta-amyloid peptide (Abeta) play central roles in the pathogenesis of Alzheimer's disease (AD). Reduction in levels of the potentially toxic Abeta 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, Abeta 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 DMT1-nonIRE, were colocalized with Abeta 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-nonIRE 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 Abeta secretion by using the SH-SY5Y cell line stably overexpressing 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 DMT1-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 Abeta 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 Abeta generation.},
  author       = {Zheng, Wei and Xin, Na and Chi, Zhi-Hong and Zhao, Bo-Lu and Zhang, Jie and Li, Jia-Yi and Wang, Zhan-You},
  issn         = {1530-6860},
  language     = {eng},
  number       = {12},
  pages        = {4207--4217},
  publisher    = {The Federation of American Societies for Experimental Biology},
  series       = {FASEB Journal},
  title        = {Divalent metal transporter 1 is involved in amyloid precursor protein processing and A{beta} generation.},
  url          = {http://dx.doi.org/10.1096/fj.09-135749},
  volume       = {23},
  year         = {2009},
}