Alzheimer's disease (AD) is a neurodegenerative disorder that affects the elderly population. Deposition of beta-amyloid (Aβ) in the brain is a hallmark of AD pathology. In our previous study, we have constructed a cell line expressing human APP695 (hAPP695) in SH-EP1 cells stably transfected with human nicotinic receptor (nAChR) α4 subunit and β2 subunit gene. In present study, we found that activation of α4β2 nAChR by nicotine and epibatidine decreased secreted Aβ level in the cell line and hippocampal neurons, but had no effects on full-length APP695 and sAPP-α. Nicotine also decreases BACE1 and PSEN1 expression, as well as ERK1 and NFκB P65 subunit expression in the cell line. Furthermore, BACE1 promoter activity is, but PSEN1 not, decreased by nicotine in the cell line. All the results suggest that activation of α4β2 nAChR decreases Aβ through regulating BACE1 transcription by ERK1-NFκB pathway. Additionally, analysis of BACE1 promoter activity by dual-luciferase reporter assay may be useful for drug screening as a high throughput method.
RNA editing is a mechanism for generating molecular diversity by altering the genetic code at the level of RNA. The 5-HT(2C) receptor is the only G protein-coupled receptor known to be edited. It has been reported that the non-edited 5-HT(2C) receptor stimulates secretion of the APP metabolite APP ectodomain (APPs). However, it remains unknown whether RNA-edited 5-HT(2C) receptors can also affect APPs secretion. In this study, cDNAs of five non-edited or partially/fully edited 5-HT(2C) receptor isoforms (INI, VNI, VNV, VSV and VGV) were stably transfected into HEK293APPSwe cells to detect the cell proliferation and APPs secretion. The results demonstrated that the overexpression of INI and VNI caused increased proliferation of host cells while VNV, VSV and VGV caused inverse effects (P < 0.01). Compared with both control and non-edited isoform INI, APPs levels were significantly increased in the four edited 5-HT(2C) receptor isoforms, VNI (P < 0.05), VNV (P < 0.05), VSV (P < 0.05) and VGV (P < 0.01). These results suggest that the RNA editing of the 5-HT(2C) receptor may affect APPs secretion through different signaling pathways related to cell growth and protein processing, and that these cell models will provide appropriate useful information to study the association between the RNA editing of the serotonin 5-HT(2C) receptor and APP metabolism.
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