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.