Abstract
Down syndrome (DS) is one of the most common genetic diseases. Patients with DS display growth delay and intellectual disabilities and develop Alzheimer’s disease (AD) neuropathology after middle age, including neuritic plaques and neurofibrillary tangles. Beta-site amyloid β precursor protein (APP) cleaving enzyme 1 (BACE1), essential for Aβ production and neuritic plaque formation, is elevated in DS patients. However, its homolog, β-site APP cleaving enzyme 2 (BACE2), functions as θ-secretase and plays a differential role in plaque formation. In this study, by using Two-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis (2D SDS-PAGE) and LC-MS/MS proteomic profiling analysis, we found that the SET oncogene protein (SET) expression was associated with BACE1 but not BACE2. SET protein was increased in BACE1 overexpressing cells and was markedly reduced in the BACE1 knockout mice. We found that the overexpression of BACE1 or SET significantly inhibited cell proliferation. Moreover, knockdown of SET in BACE1 overexpression cells significantly rescued BACE1-induced cell growth suppression. Furthermore, both BACE1 and SET protein levels were increased in Down syndrome patients. It suggests that BACE1 overexpression-induced SET upregulation may contribute to growth delay and cognitive impairment in DS patients. Our work provides a new insight that BACE1 overexpression not only promotes neuritic plaque formation but may also potentiate neurodegeneration mediated by SET elevation in Alzheimer-associated dementia in DS.
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Acknowledgments
We thank CHiBI Proteomics Core Facility of University of British Columbia for mass spectrometric analysis of the 2D gel dots. We thank Dr. Suzanne C. Perry for the discussions. This work is supported by the Canadian Institutes for Health Research (CIHR) (MOP-97825 and TAD-117948), the National Natural Science Foundation of China (NSFC) (NSFC81161120498), and the Jack Brown and Family Alzheimer’s Research Foundation. WS is the holder of the Tier 1 Canada Research Chair in Alzheimer’s disease. XZ is the recipient of the Arthur and June Willms Fellowship. XD is supported by the Chinese Scholarship Council awards.
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X. Zhang, Y. Wu and X. Duan contributed equally to this work.
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Zhang, X., Wu, Y., Duan, X. et al. Upregulation of SET Expression by BACE1 and its Implications in Down Syndrome. Mol Neurobiol 51, 781–790 (2015). https://doi.org/10.1007/s12035-014-8782-x
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DOI: https://doi.org/10.1007/s12035-014-8782-x