Abstract
Down syndrome (DS), caused by trisomy of chromosome 21, is one of the most common genetic disorders. Patients with DS display growth retardation and inevitably develop characteristic Alzheimer’s disease (AD) neuropathology, including neurofibrillary tangles and neuritic plaques. The expression of amyloid precursor protein (APP) is increased in both DS and AD patients. To reveal the function of APP and elucidate the pathogenic role of increased APP expression in DS and AD, we performed gene expression profiling using microarray method in human cells overexpressing APP. A set of genes are significantly altered, which are involved in cell cycle, cell proliferation and p53 signaling. We found that overexpression of APP inhibits cell proliferation. Furthermore, we confirmed that the downregulation of two validated genes, PSMA5 and PSMB7, inhibits cell proliferation, suggesting that the downregulation of PSMA5 and PSMB7 is involved in APP-induced cell proliferation impairment. Taken together, this study suggests that APP regulates global gene expression and increased APP expression inhibits cell proliferation. Our study provides a novel insight that APP overexpression may contribute to the growth impairment in DS patients and promote AD pathogenesis by inhibiting cell proliferation including neural stem cell proliferation and neurogenesis.
Highlights
Patients with Down syndrome (DS) display growth retardation, cardiac and gastrointestinal abnormalities, immune system defects and inevitably develop characteristic Alzheimer’s disease (AD) neuropathology including neuritic plaques and neurofibrillary tangles
amyloid precursor protein (APP) expression is increased in both DS patients and AD patients[9]
To investigate the role of APP overexpression in the regulation of global gene expression, the wildtype human APP was stably transfected into Human embryonic kidney (HEK) 293 cells as HAW cells
Summary
Patients with DS display growth retardation, cardiac and gastrointestinal abnormalities, immune system defects and inevitably develop characteristic Alzheimer’s disease (AD) neuropathology including neuritic plaques and neurofibrillary tangles. APP expression is increased in both DS patients and AD patients, contributing to an increase of Aβ generation and neuritic plaque formation[3,4,5,6,7,8,9,10]. In addition to promoting Aβ generation and neuritic plaque formation, the pathogenic role of increased APP expression in DS and AD remains elusive. APP, a type I transmembrane protein, is predominantly cleaved by α -secretase, generating an N-terminal secreted soluble APPα (sAPPα ) and a C-terminal 83-amino acid fragment (C83). APP is cleaved by BACE2 (beta-site APP cleaving enzyme 2), a θ -secretase, to generate a C-terminal fragment of 80 amino acids followed by γ -secretase cleavage[20,21,22]. The evidence indicates that APP is a multifunctional protein by itself and the proteolytic fragments of APP possess major cellular functions
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