The role of copper and the copper-related protein CUTA in mediating APP processing and Aβ generation

Ping Hou, Guiying Liu, Yingjun Zhao, Zhun Shi, Qiuyang Zheng, Guojun Bu, Huaxi Xu, Yun wu Zhang

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

One major pathologic hallmark and trigger of Alzheimer's disease (AD) is overproduction and accumulation of β-amyloid (Aβ) species in the brain. Aβ is derived from β-amyloid precursor protein (APP) through sequential cleavages by β- and γ-secretases. Abnormal copper homeostasis also contributes to AD pathogenesis. Recently, we find that a copper-related protein, CutA divalent cation tolerance homolog of Escherichia coli (CUTA), interacts with the β-secretase β-site APP cleaving enzyme 1 (BACE1) and inhibits APP β-processing and Aβ generation. Herein, we further found that overexpression of CUTA increases intracellular copper level, whereas copper treatments promote CUTA expression. We also confirmed that copper treatments promote APP expression and Aβ secretion. In addition, copper treatments promoted the increase of Aβ secretion induced by CUTA downregulation but had no effect on CUTA-β-site APP cleaving enzyme 1 interaction. On the other hand, CUTA overexpression ameliorated copper-induced Aβ secretion but had no effect on APP expression. Moreover, we found that Aβ treatments can reduce both CUTA and copper levels in mouse primary neurons. Consistently, both CUTA and copper levels were decreased in the hippocampus of APP/PS1 AD mouse brain. Together, our results reveal a reciprocal modulation of copper and CUTA and suggest that both regulate Aβ generation through different mechanisms, although Aβ mutually affects copper and CUTA levels.

Original languageEnglish (US)
Pages (from-to)1310-1315
Number of pages6
JournalNeurobiology of aging
Volume36
Issue number3
DOIs
StatePublished - Mar 1 2015

Keywords

  • Alzheimer's disease
  • Copper
  • CutA divalent cation tolerance homolog of E.coli
  • β-amyloid
  • β-amyloid precursor protein

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

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