The amyloid precursor protein controls PIKfyve function


While the Amyloid Precursor Protein (APP) plays a central role in Alzheimer's disease, its cellular function still remains largely unclear. It was our goal to establish APP function which will provide insights into APP's implication in Alzheimer's disease. Using our recently developed proteo-liposome assay we established the interactome of APP's intracellular domain (known as AICD), thereby identifying novel APP interactors that provide mechanistic insights into APP function. By combining biochemical, cell biological and genetic approaches we validated the functional significance of one of these novel interactors. Here we show that APP binds the PIKfyve complex, an essential kinase for the synthesis of the endosomal phosphoinositide phosphatidylinositol-3,5-bisphosphate. This signalling lipid plays a crucial role in endosomal homeostasis and receptor sorting. Loss of PIKfyve function by mutation causes profound neurodegeneration in mammals. Using C. elegans genetics we demonstrate that APP functionally cooperates with PIKfyve in vivo. This regulation is required for maintaining endosomal and neuronal function. Our findings establish an unexpected role for APP in the regulation of endosomal phosphoinositide metabolism with dramatic consequences for endosomal biology and important implications for our understanding of Alzheimer's disease.

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Divisions: College of Health & Life Sciences
College of Health & Life Sciences > School of Biosciences
College of Health & Life Sciences > School of Biosciences > Cellular and Molecular Biomedicine
Additional Information: © 2015 Balklava et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: Alzheimer Research UK ARUK-PHD-12/13; BBSRC BB/K014862/1 (TW and ZB); Royal Society (ZB); Deutsche Forschungsgemeinschaft TRR 83/1-2010, HO 2584/1-1, HO 2584/2-1, HO 2584/6-1, HO 2584/8-1, HO 2584/9-1 (BH); BBSRC (BB/J014834/1). LM is funded by a BBSRC DTP (BB/J014478/1).
Uncontrolled Keywords: Agricultural and Biological Sciences(all),Biochemistry, Genetics and Molecular Biology(all),Medicine(all)
Publication ISSN: 1932-6203
Last Modified: 19 Jan 2024 08:06
Date Deposited: 02 Jul 2015 13:15
Full Text Link: http://journals ... al.pone.0130485
Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2015-06-30
Authors: Balklava, Zita (ORCID Profile 0000-0001-9039-9710)
Niehage, Christian
Currinn, Heather
Mellor, Laura
Guscott, Benjamin
Poulin, Gino
Hoflack, Bernard
Wassmer, Thomas



Version: Published Version

License: Creative Commons Attribution

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