A mobile APP for sharing contacts on your cell

Rebeck, G. William; Pak, Daniel T.S.

doi:10.1111/jnc.14115

Cited by 1 publication

(1 citation statement)

References 10 publications

(26 reference statements)

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“…It is over 30 years since the APP gene was molecularly cloned and the protein it encoded for found to have characteristics of a glycosylated cell surface receptor 1 . Recently, there has been a resurgence of interest in the role of APP as a receptor and as a cell adhesion protein (reviewed in 8 and 45 – 47 , respectively). The data we present here indicate that APP, if not a true receptor protein per se , can act as a component of both the Wnt-β-catenin and Wnt-PCP co-receptor protein complexes.…”

Section: Discussionmentioning

confidence: 99%

A role for APP in Wnt signalling links synapse loss with β-amyloid production

et al. 2018

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In Alzheimer’s disease (AD), the canonical Wnt inhibitor Dickkopf-1 (Dkk1) is induced by β-amyloid (Aβ) and shifts the balance from canonical towards non-canonical Wnt signalling. Canonical (Wnt-β-catenin) signalling promotes synapse stability, while non-canonical (Wnt-PCP) signalling favours synapse retraction; thus Aβ-driven synapse loss is mediated by Dkk1. Here we show that the Amyloid Precursor Protein (APP) co-activates both arms of Wnt signalling through physical interactions with Wnt co-receptors LRP6 and Vangl2, to bi-directionally modulate synapse stability. Furthermore, activation of non-canonical Wnt signalling enhances Aβ production, while activation of canonical signalling suppresses Aβ production. Together, these findings identify a pathogenic-positive feedback loop in which Aβ induces Dkk1 expression, thereby activating non-canonical Wnt signalling to promote synapse loss and drive further Aβ production. The Swedish familial AD variant of APP (APPSwe) more readily co-activates non-canonical, at the expense of canonical Wnt activity, indicating that its pathogenicity likely involves direct effects on synapses, in addition to increased Aβ production. Finally, we report that pharmacological inhibition of the Aβ-Dkk1-Aβ positive feedback loop with the drug fasudil can restore the balance between Wnt pathways, prevent dendritic spine withdrawal in vitro, and reduce Aβ load in vivo in mice with advanced amyloid pathology. These results clarify a relationship between Aβ accumulation and synapse loss and provide direction for the development of potential disease-modifying treatments.

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