Abstract
BackgroundIcaritin (ICT) is a prenylflavonoid derivative from Epimedium brevicornum Maxim. ICT has been shown to have neuroprotective effects. We investigate how ICT affects secretion of amyloid precursor protein (APP).MethodsWe exposed APP-PS1-HEK293 cells to ICT to investigate its effect on beta-site amyloid cleaving enzyme (BACE)1. Cell viability was evaluated by MTT and lactate dehydrogenase (LDH) assays. The half-maximal inhibitory concentration (IC50) of ICT for BACE1 was measured using fluorescence resonance energy transfer. Effects of ICT on the mRNA expression of APP were assessed by quantitative polymerase chain reaction, and protein expression was measured by western blotting and immunofluorescence.ResultsIcaritin inhibited BACE1 activity and IC50 was 5.70 ± 1.09 μM. Compared with the control group, at ICT concentrations of 5 μM and 10 μM, the viability increased and LDH leakage decreased in APP-PS1-293 cells. Also, mRNA expression of A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) increased, while that of BACE1 and presenilin-1 (PS1) decreased, upon ICT treatment. Western blotting and immunofluorescence confirmed that protein expression of ADAM10, BACE1 and PS1 showed the same trend. Expression of the APP fragments sAPPβ and C-terminal fragment β decreased, while that of sAPPα increased, upon ICT treatment. Expression of amyloid β peptides in APP-PS1-HEK293 cells was lower in ICT-treated groups compared with that in the control group.ConclusionsIcaritin, as a BACE1 inhibitor, inhibits APP secretion in APP-PS1-HEK293 cells by impeding the amyloidogenic pathway.
Highlights
Alzheimer’s disease (AD) is a degenerative disease of the central nervous system characterized by progressive cognitive dysfunction and behavioral impairment
Protective effect of ICT in amyloid precursor protein (APP)-PS1-293 cells Cell viability was measured by the MTT assay and cell-membrane damage was determined according to lactate dehydrogenase (LDH) leakage
Compared with the control group, at ICT concentrations of 5 mM and 10 mM, the viability increased and LDH leakage decreased in APP-PS1-293 cells
Summary
Alzheimer’s disease (AD) is a degenerative disease of the central nervous system characterized by progressive cognitive dysfunction and behavioral impairment. According to a report from Alzheimer’s Disease International, there are ~9.5 million dementia patients in China currently and this number may exceed 16 million by 2030 (Alzheimer’s Disease International, 2016). Amyloid-β peptides (AβPs) are generated through sequential cleavage of amyloid precursor protein (APP) by beta-site amyloid cleaving enzyme (BACE) and γ-secretase (presenilin-1 (PS1)), which play pivotal roles in AD pathogenesis (Querfurth & LaFerla, 2010). Methods: We exposed APP-PS1-HEK293 cells to ICT to investigate its effect on beta-site amyloid cleaving enzyme (BACE). Compared with the control group, at ICT concentrations of 5 mM and 10 mM, the viability increased and LDH leakage decreased in APP-PS1-293 cells. MRNA expression of A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) increased, while that of BACE1 and presenilin-1 (PS1) decreased, upon ICT treatment. Expression of amyloid β peptides in APP-PS1HEK293 cells was lower in ICT-treated groups compared with that in the control group. Conclusions: Icaritin, as a BACE1 inhibitor, inhibits APP secretion in APP-PS1HEK293 cells by impeding the amyloidogenic pathway
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