. APP is phosphorylated by TrkA and regulates NGF/TrkA signaling. J Neurosci. 2011 Aug 17;31(33):11756-61. PubMed.

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  1. This study by Matrone et al. establishes a reciprocal, functional link between the post-translational modification of the amyloid-β precursor protein (APP) and the NGF/TrkA signaling pathway that could be relevant to Alzheimer’s disease (AD). This article is also important for at least two other reasons. First, together with other papers from D’Adamio’s lab (1-10), it draws attention to the relevance of APP phosphorylation for the normal function of APP and pathogenesis of AD.

    APP is phosphorylated at multiple sites within its intracellular domain; the phosphorylating kinases, and the mechanisms of phosphorylation, are just beginning to be elucidated (5,7,11-13).

    In addition, the article tacitly touches the controversy of whether APP is—or is not—a key regulator of intraneuronal transport processes (14). The paper does not directly address the possibility that APP regulates NGF/TrkA signaling through the regulation of transport of signaling proteins, nor does it address whether the changes in processing of APP via neurotrophic signaling involves altered trafficking of APP. Nevertheless, the findings that APP and TrkA do interact, and regulate each other’s subcellular distribution, as this paper shows, certainly point towards such mechanisms. We also note that APP, its processing machinery, and TrkA have been previously tied together in a common transport pathway (15). Thus, it becomes clear that alterations in intracellular trafficking could be part of AD pathogenesis. Of course, the dilemma is whether the abnormal transport causes the alterations in APP post-translational modifications (including enhancement of its amyloidogenic processing), or whether the altered function of APP leads to abnormal transport.

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