title: Divalent cation tolerance protein binds to β-secretase and inhibits the processing of amyloid precursor protein.
abstract: The deposition of amyloid-beta is a pathological hallmark of Alzheimer's disease. Amyloid-beta is derived from amyloid precursor protein through sequential proteolytic cleavages by β-secretase (beta-site amyloid precursor protein-cleaving enzyme 1) and γ-secretase. To further elucidate the roles of beta-site amyloid precursor protein-cleaving enzyme 1 in the development of Alzheimer's disease, a yeast two-hybrid system was used to screen a human embryonic brain cDNA library for proteins directly interacting with the intracellular domain of beta-site amyloid precursor protein-cleaving enzyme 1. A potential beta-site amyloid precursor protein-cleaving enzyme 1-interacting protein identified from the positive clones was divalent cation tolerance protein. Immunoprecipitation studies in the neuroblastoma cell line N2a showed that exogenous divalent cation tolerance protein interacts with endogenous beta-site amyloid precursor protein-cleaving enzyme 1. The overexpression of divalent cation tolerance protein did not affect beta-site amyloid precursor protein-cleaving enzyme 1 protein levels, but led to increased amyloid precursor protein levels in N2a/APP695 cells, with a concomitant reduction in the processing product amyloid precursor protein C-terminal fragment, indicating that divalent cation tolerance protein inhibits the processing of amyloid precursor protein. Our experimental findings suggest that divalent cation tolerance protein negatively regulates the function of beta-site amyloid precursor protein-cleaving enzyme 1. Thus, divalent cation tolerance protein could play a protective role in Alzheimer's disease.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Department of Biomedical Sciences, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian Province, China.
authors.forename: Runzhong
authors.initials: R
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Department of Biomedical Sciences, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian Province, China.
authors.forename: Haibo
authors.initials: H
authors.lastname: Hou
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Department of Biomedical Sciences, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian Province, China.
authors.forename: Xuelian
authors.initials: X
authors.lastname: Yi
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Department of Biomedical Sciences, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian Province, China.
authors.forename: Shanwen
authors.initials: S
authors.lastname: Wu
authors.affiliation: Xiamen Maternal and Child Health Hospital, Xiamen 361003, Fujian Province, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Zeng
keywords: Alzheimer's disease; amyloid precursor protein; amyloid precursor protein C-terminal fragment; amyloid-beta; beta-site amyloid precursor protein-cleaving enzyme 1; brain injury; grants-supported paper; interaction; neural regeneration; neurodegenerative diseases; neuroregeneration; western blot; yeast two-hybridization; β-secretase