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Abstract

The �³-secretase has been a therapeutically target for its key role in cleaving APP to generate �²-Amyloid (A�²), the primary constituents of senile plaques and a hallmark of Alzheimerâ��s Disease (AD) pathology. Recently, �³-secretase associating proteins showed promising role in specifically modulating APP processing while sparing Notch signaling; however, the underlying mechanism is still unclear. A Co-Immunoprecipitation (Co-IP) coupled with mass spectrometry proteomic assay for Presenilin1 (PS1, the catalytic subunit of �³-secretase) was firstly conducted to find more �³-secretase associating proteins. Gene ontology analysis of these results identified Rab21 as a potential PS1 interacting protein, and the interaction between them was validated by reciprocal Co-IP and immunofluorescence assay. Then, molecular and biochemical methods were used to investigate the effect of Rab21 on APP processing. Results showed that overexpression of Rab21 enhanced A�² generation, while silencing of Rab21 reduced the accumulation of A�², which resulted due to change in �³- secretase activity rather than �±- or �²-secretase. Finally, we demonstrated that Rab21 had no effect on �³-secretase complex synthesis or metabolism but enhanced PS1 endocytosis and translocation to late endosome/lysosome. In conclusion, we identified a novel �³-secretase-associating protein Rab21 and illustrate that Rab21 promotes �³-secretase internalization and translocation to late endosome/lysosome. Moreover, silencing of Rab21 decreases the �³-secretase activity in APP processing thus production of A�². All these results open new gateways towards the understanding of �³-secretase-associating proteins in APP processing and make inhibition of Rab21 a promising strategy for AD therapy. hqing@bit.edu.cn

Biography