School of Chinese Medicine
Alzheimer disease (AD) is the most common neurodegenerative disease characterized by the deposition of amyloid plaque in the brain. The autophagy-associated PIK3C3-containing phosphatidylinositol 3-kinase (PtdIns3K) complex has been shown to interfere with APP metabolism and amyloid beta peptide (Aβ) homeostasis via poorly understood mechanisms. Here we report that NRBF2 (nuclear receptor binding factor 2), a key component and regulator of the PtdIns3K, is involved in APP-CTFs homeostasis in AD cell models. We found that NRBF2 interacts with APP in vivo and its expression levels are reduced in hippocampus of 5XFAD AD mice; we further demonstrated that NRBF2 overexpression promotes degradation of APP C-terminal fragments (APP-CTFs), and reduces Aβ1-40 and Aβ1-42 levels in human mutant APP-overexpressing cells. Conversely, APP-CTFs, Aβ1-40 and Aβ1-42 levels were increased in Nrbf2knockdown or nrbf2 knockout cells. Furthermore, NRBF2 positively regulates autophagy in neuronal cells and NRBF2-mediated reduction of APP-CTFs levels is autophagy dependent. Importantly, nrbf2 knockout attenuates the recruitment of APP and APP-CTFs into phagophores and the sorting of APP and APP-CTFs into endosomal intralumenal vesicles, which is accompanied by the accumulation of the APP and APP-CTFs into RAB5-positive early endosomes. Collectively, our results reveal the potential connection between NRBF2 and the AD-associated protein APP by showing that NRBF2 plays an important role in regulating degradation of APP-CTFs through modulating autophagy.
Aβ, Alzheimer's disease, APP, autophagy, class III phosphatidylinositol 3-kinase (PtdIns3K), NRBF2
Source Publication Title
Taylor & Francis
This is an Accepted Manuscript of an article published by Taylor & Francis in Autophagy in 2017, available online: http://www.tandfonline.com/10.1080/15548627.2017.1379633.
This study was supported by the grants of NSFC-31500831, EF001/ICMS-LJH/2015/HKBU, SKL-QRCM-2014-2016, FDCT-022/2015/A1, FDCT-092-2015-A3 and MYRG2016-00119-ICMS-QRCM (to Jiahong Lu) and the grants of RGC/HKBU-121009/14, HMRF12132091, HMRF14150811, RC-IRMS/15-16/04, FRG II/15-16/034 and FRG II/16-17/018 (to Min Li). The authors would like to thank Dr. King-Ho Cheung and Dr. Benjamin Tong for their kind technique support and Dr. Martha Dahlen for her English editing of this manuscript.
Link to Publisher's Edition
Yang, C., Cai, C., Song, J., Tan, J., Druairajan, S., Iyaswamy, A., Wu, M., Chen, L., Yue, Z., Li, M., & Lu, J. (2017). NRBF2 is involved in the autophagic degradation process of APP-CTFs in Alzheimer disease models. Autophagy, 13 (12), 2028-2040. https://doi.org/10.1080/15548627.2017.1379633