Abstract
The Amyloid Precursor Protein (APP) and its homologues are transmembrane proteins required for various aspects of neuronal development and activity, whose molecular function is unknown. Specifically, it is unclear whether APP acts as a receptor, and if so what its ligand(s) may be. We show that APP binds the Wnt ligands Wnt3a and Wnt5a and that this binding regulates APP protein levels. Wnt3a binding promotes full-length APP (flAPP) recycling and stability. In contrast, Wnt5a promotes APP targeting to lysosomal compartments and reduces flAPP levels. A conserved Cysteine-Rich Domain (CRD) in the extracellular portion of APP is required for Wnt binding, and deletion of the CRD abrogates the effects of Wnts on flAPP levels and trafficking. Finally, loss of APP results in increased axonal and reduced dendritic growth of mouse embryonic primary cortical neurons. This phenotype can be cell-autonomously rescued by full length, but not CRD-deleted, APP and regulated by Wnt ligands in a CRD-dependent manner.
Highlights
The Amyloid Precursor Protein (APP) is the precursor that generates the Ab peptide, whose accumulation is associated with Alzheimer’s disease (AD; Selkoe and Hardy, 2016)
We show that APP binds both canonical and non-canonical Wnt ligands via a conserved Cysteine-Rich Domain (CRD) and that this binding regulates the levels of full-length APP by regulating its intracellular trafficking from early endosomes to the trans Golgi network versus the lysosome
For example the growth factor like domain (GFLD) in the E1 region of APP could act as a ligand-binding site, and disulfide bridges within the same E1 area could further facilitate ligand-induced signal transduction by stabilizing the structure of APP ectodomain (Reinhard et al, 2005; Rossjohn et al, 1999; Stahl et al, 2014; Kaden et al, 2009)
Summary
The Amyloid Precursor Protein (APP) is the precursor that generates the Ab peptide, whose accumulation is associated with Alzheimer’s disease (AD; Selkoe and Hardy, 2016). During Drosophila brain development the fly homolog of APP, called APPL, functions as key component of the neuronal Wnt-PCP signaling pathway and regulates the axonal outgrowth in fly mushroom body (Soldano et al, 2013). Both mammalian APP and fly APPL contain a Cysteine-Rich Domain (CRD) in the ectodomain of APP whose Cysteine distribution resembles that of the Wnt Tyrosine-protein kinase receptor Ror (Coburger et al, 2013; Oishi et al, 2003), suggesting the intriguing possibility that APP may itself be a receptor for Wnt family member. APP trafficking and expression is regulated by Wnts through the CRD, which in turn is required for APP to regulate axonal and dendritic growth and branching
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