title: Role of copper and the copper-related protein CUTA in mediating APP processing and Aβ generation.
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.
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, China; School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Hou
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, China.
authors.forename: Guiying
authors.initials: G
authors.lastname: Liu
authors.affiliation: Degenerative Disease Research Program, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
authors.forename: Yingjun
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, China.
authors.forename: Zhun
authors.initials: Z
authors.lastname: Shi
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, China.
authors.forename: Qiuyang
authors.initials: Q
authors.lastname: Zheng
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, China.
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, China; Degenerative Disease Research Program, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
authors.forename: Huaxi
authors.initials: H
authors.lastname: Xu
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, China. Electronic address: yunzhang@xmu.edu.cn.
authors.forename: Yun-wu
authors.initials: YW
authors.lastname: Zhang
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology*; D053829:Amyloid Precursor Protein Secretases / Q000502:physiology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000502:physiology; D002478:Cells, Cultured; D003300:Copper / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D015870:Gene Expression; D006706:Homeostasis; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D008810:Mice, Inbred C57BL; D011817:Rabbits
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C416667:CUTA protein, human; D008565:Membrane Proteins; D003300:Copper; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: Alzheimer's disease; Copper; CutA divalent cation tolerance homolog of E. coli; β-amyloid; β-amyloid precursor protein