title: Upregulation of SET expression by BACE1 and its implications in Down syndrome.
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.
authors.affiliation: Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, Graduate Program in Neuroscience, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada.
authors.forename: Xiaozhu
authors.initials: X
authors.lastname: Zhang
authors.forename: Yili
authors.initials: Y
authors.lastname: Wu
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Duan
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zou
authors.forename: Mingming
authors.initials: M
authors.lastname: Zhang
authors.forename: Shuting
authors.initials: S
authors.lastname: Zhang
authors.forename: Fang
authors.initials: F
authors.lastname: Cai
authors.forename: Weihong
authors.initials: W
authors.lastname: Song
mesh_terms: D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D004314:Down Syndrome / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D056488:Histone Chaperones / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D056488:Histone Chaperones; C513473:SET protein, human; D014157:Transcription Factors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human