Amyloid Precursor Protein Binding Protein-1 Is Up-regulated in Brains of Tg2576 Mice

Hyun Jung Yang; Yuyoung Joo; Bo-Hyun Hong; Sung-Ji Ha; Ran-Sook Woo; Sang Hyung Lee; Yoo-Hun Suh; Hye-Sun Kim

doi:10.4196/kjpp.2010.14.4.229

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Yang, Joo, Hong, Ha, Woo, Lee, Suh, and Kim: Amyloid Precursor Protein Binding Protein-1 Is Up-regulated in Brains of Tg2576 Mice

Original Article

Korean J Physiol Pharmacol 2010;14(4):229-233.

Published online: 18 February 2010

DOI: https://doi.org/10.4196/kjpp.2010.14.4.229

Amyloid Precursor Protein Binding Protein-1 Is Up-regulated in Brains of Tg2576 Mice

Hyun Jung Yang^1,^∗, Yuyoung Joo^2,^∗, Bo-Hyun Hong², Sung-Ji Ha², Ran-Sook Woo³, Sang Hyung Lee⁴, Yoo-Hun Suh², Hye-Sun Kim^2,^5,

¹Department of Food and Nutrition, Kookmin University College of Natural Sciences, Seoul 136-702, Korea

²Department of Pharmacology, Seoul National University College of Medicine, Seoul 110-799, Korea

³Department of Anatomy and Neuroscience, College of Medicine, Eulji University, Daejeon 301-746, Korea

⁴Department of Neurosurgery, Seoul National University College of Medicine, Seoul 110-799, Korea

⁵Department of Pharmacology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Sungnam 463-707, Korea

Corresponding to: Hye-Sun Kim, Departments of Pharmacology, Biomedical Sciences, College of Medicine, Seoul National University, 28, Yeongeon-dong, Jongno-gu, Seoul 110-799, Korea. (Tel) 82-2-740-8298, (Fax) 82-2-741-8298, (E-mail) hyisun@snu.ac.kr

^∗ These two authors equally contributed to this study.

Received 17 July 2010 Revised 27 July 2010 Accepted 5 August 2010

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Amyloid precursor protein binding protein-1 (APP-BP1) binds to the carboxyl terminus of amyloid precursor protein and serves as a bipartite activation enzyme for the ubiquitin-like protein, NEDD8. Previously, it has been reported that APP-BP1 rescues the cell cycle S-M checkpoint defect in Ts41 hamster cells, that this rescue is dependent on the interaction of APP-BP1 with hUba3. The exogenous expression of APP-BP1 in neurons has been reported to cause DNA synthesis and apoptosis via a signaling pathway that is dependent on APP-BP1 binding to APP. These results suggest that APP-BP1 overexpression contributes to neurodegeneration. In the present study, we explored whether APP-BP1 expression was altered in the brains of Tg2576 mice, which is an animal model of Alzheimer's disease. APP-BP1 was found to be up-regulated in the hippocampus and cortex of 12 month-old Tg2576 mice compared to age-matched wild-type mice. In addition, APP-BP1 knockdown by siRNA treatment reduced cullin-1 neddylation in fetal neural stem cells, suggesting that APP-BP1 plays a role in cell cycle progression in the cells. Collectively, these results suggest that increased expression of APP-BP1, which has a role in cell cycle progression in neuronal cells, contributes to the pathogenesis of Alzheimer's disease.

Keywords: Amyloid precursor protein binding protein-1, Amyloid precursor protein, Alzheimer's disease, cell cycle, Tg2576 mice

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Fig. 1.

APP-BP1 protein level was up-regulated in the hippocampus from 12 month-old Tg2576 mice. (A) APP-BP1 protein level was examined by western blotting in the hippocampus from 6-, 12- and 18-month-old Tg 2576 and wild-type mice. This blot is a representative of 4 independent experiments. (B) Densitometric analysis was also performed. Data represent mean±SEM. ^∗p<0.05 compared with 6 month-old wild type mice (n=4) and ^#p<0.05 compared with 12 month-old wild type mice, by one-way ANOVA followed by Duncan's post hoc test.

Fig. 2.

APP-BP1 immunoreactivities are increased in the cortex and hippocampus from 12-month-old wild-type and Tg2576 mice. The fixed brains from 12-month-old wild type and Tg2576 mice (n=5) in 10% neutral buffered formalin for 48 h were dehydrated and embedded in paraffin. (A) The fluorescent immunohistochemistry was performed in the cortex with the anti-APP-BP1 antibody for 2 h, which was then visualized using a Cy3-conjugated secondary antibody. DAPI counter staining was performed. Images were collected using the LSM 510 program on a Zeiss confocal microscope. This figure is a representative of 5 independent experiments. Scale bars=25 μm. (B) Immunoreactivities of APP-BP1 was examined in the dentate gyrus of 12 month-old wild type and Tg2576 mice. IHC was performed using a Vectastain avidin-biotin complex elite kit. Peroxidase stained sections were examined under a light microscope (BX51TF; Olympus Optical Co., Japan) equipped with an exposure control unit (PM-CB20) and a camera (CPM-C35DX). Scale bars=50μm. (C) Quantative analysis for (B) was performed by calculating APP-BP1 immunoreactive cells per section from 5 independent samples (^∗∗p<0.01 by Student's t-test).

Fig. 3.

APP-BP1 knockdown reduced Cul-1 neddylation in fetal neural stem cells. (A) After treatment of fetal neural stem cells with 10 nM non-targeting and APP-BP1 siRNAs for 72 h, APP-BP1 protein levels were examined by western blotting. Densitometric analysis was also performed. Data represent mean±SEM. ^∗p<0.05 compared with non-treated cells, by one-way ANOVA followed by Duncan's post hoc test. (B) After treatment with siRNAs in fetal neural stem cells (passage 8) for 72 h, neddylated Cul-1 was examined by immunoprecipitation of Cul-1 followed by western blotting for NEDD8.

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