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      NRBF2 is involved in the autophagic degradation process of APP-CTFs in Alzheimer disease models

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          ABSTRACT

          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 Aβ 1–40 and Aβ 1-42 levels in human mutant APP-overexpressing cells. Conversely, APP-CTFs, Aβ 1–40 and Aβ 1-42 levels were increased in Nrbf2 knockdown 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.

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          Author and article information

          Journal
          Autophagy
          Autophagy
          KAUP
          kaup20
          Autophagy
          Taylor & Francis
          1554-8627
          1554-8635
          2017
          5 October 2017
          : 13
          : 12
          : 2028-2040
          Affiliations
          [a ] Mr. and Mrs. Ko Chi Ming Centre for Parkinson's Disease Research, School of Chinese Medicine, Hong Kong Baptist University , Hong Kong SAR, China
          [b ] State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau , Taipa, Macau SAR, China
          [c ] State Key Laboratory of Medical Genetics, Xiangya Medical School, Central South University , Changsha, Hunan, China
          [d ] Department of Neurology and Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai , New York, NY, USA
          Author notes
          Min Li limin@ 123456hkbu.edu.hk , School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Kowloon, Hong Kong SAR, China
          Jia-Hong Lu jiahonglu@ 123456umac.mo , State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Science, University of Macau, Room 7015, N22 Building, Avenida da Universidade, Taipa, Macau SAR, China.

          Supplemental data for this article can be accessed on the http://dx.doi.org/10.1080/15548627.2017.1379633

          Article
          PMC5788544 PMC5788544 5788544 1379633
          10.1080/15548627.2017.1379633
          5788544
          28980867
          473a83d2-e45c-4883-8833-ef66ddda9256
          © 2017 Taylor & Francis
          History
          : 15 August 2016
          : 14 August 2017
          : 8 September 2017
          Page count
          Figures: 8, Tables: 0, References: 57, Pages: 13
          Categories
          Brief Report

          NRBF2,class III phosphatidylinositol 3-kinase (PtdIns3K),autophagy,APP,Alzheimer's disease,

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