Abstract
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.
Highlights
The transmembrane protein Amyloid Precursor Protein (APP, NCBI: NM_000484) is the central player in Alzheimer’s disease, as patients with mutations in the APP gene develop a familial form of Alzheimer’s disease [1, 2]
For understanding the elusive physiological role of APP we studied the interactome of APP's intracellular domain using an in-vitro reconstitution system that we have recently established [27]
Combining AICD proteo-liposomes with label-free mass spectrometry [30] we established the interactome of APP's intracellular domain and, surprisingly, found all three subunits of the mammalian PIKfyve complex, namely PIKfyve (NCBI: NM_015040), Vac14 (NCBI: NM_018052) and Fig 4 (NCBI: NM_014845) to associate with APP's intracellular domain (Fig 1)
Summary
The transmembrane protein Amyloid Precursor Protein (APP, NCBI: NM_000484) is the central player in Alzheimer’s disease, as patients with mutations in the APP gene develop a familial form of Alzheimer’s disease [1, 2]. APP is processed by beta and gamma secretases into three main fragments: the beta amyloid peptide (approximately 40 amino acids in length) which is released from neurons, the extracellular domain of APP (sAPPb) and the intracellular domain termed AICD. Cleavage of APP by the gamma secretase complex is instrumental in Alzheimer’s disease as documented by the identification of familial Alzheimer’s disease mutations in gamma secretase complex subunits (reviewed in [3]).
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