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

Elliott, Christina; Rojo, Ana, I; Ribe, Elena; Broadstock, Martin; Xia, Weiming; Morin, Peter; Semenov, Mikhail; Baillie, George; Cuadrado, Antonio; Al-Shawi, Raya; Ballard, Clive G.; Simons, Paul; Killick, Richard

TRANSLATIONAL PSYCHIATRY
2018
VL / 8 - BP / - EP /
abstract
In Alzheimer's disease (AD), the canonical Wnt inhibitor Dickkopf-1 (Dkk1) is induced by beta-amyloid (A beta) and shifts the balance from canonical towards non-canonical Wnt signalling. Canonical (Wnt-beta-catenin) signalling promotes synapse stability, while non-canonical (Wnt-PCP) signalling favours synapse retraction; thus A beta-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 A beta production, while activation of canonical signalling suppresses A beta production. Together, these findings identify a pathogenic-positive feedback loop in which A beta induces Dkk1 expression, thereby activating non-canonical Wnt signalling to promote synapse loss and drive further A beta production. The Swedish familial AD variant of APP (APP(Swe)) 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 A beta production. Finally, we report that pharmacological inhibition of the A beta-Dkk1-AA beta positive feedback loop with the drug fasudil can restore the balance between Wnt pathways, prevent dendritic spine withdrawal in vitro, and reduce A beta load in vivo in mice with advanced amyloid pathology. These results clarify a relationship between AP accumulation and synapse loss and provide direction for the development of potential disease-modifying treatments.

AccesS level

Green published, Gold, Green accepted

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