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.

中文翻译：

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淀粉样前体蛋白是保守的Wnt受体

淀粉样前体蛋白（APP）及其同系物是神经元发育和活性各个方面所需的跨膜蛋白，其分子功能尚不清楚。具体而言，尚不清楚APP是否充当受体，以及是否充当其配体。我们显示APP结合Wnt配体Wnt3a和Wnt5a，并且这种结合调节APP蛋白水平。Wnt3a结合可促进全长APP（flAPP）的回收利用和稳定性。相反，Wnt5a促进APP靶向溶酶体区室并降低flAPP水平。Wnt结合需要APP胞外部分中的保守半胱氨酸富集域（CRD），并且删除CRD可以消除Wnts对flAPP水平和运输的影响。最后，APP的丧失导致小鼠胚胎初级皮层神经元的轴突增加和树突生长减少。该表型可以通过全长细胞自主挽救，但不能删除CRD。