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A role for APP in Wnt signalling links synapse loss with β-amyloid production: Aβ synaptotoxicity drives Aβ production

Research output: Contribution to journalArticle

Christina Louise Elliott, Ana I Rojo, Elena Ribe, Martin Broadstock, Weiming Xia, Peter Mornin, mMikhail Semenov, George Baillie, Antonio Cuadrado, Raya Al-Shawi, Clive Gerald Ballard, Paul Simons, Richard Killick

Original languageEnglish
Article number179
JournalTranslational psychiatry
Volume8
Issue number1
Early online date24 Jul 2018
DOIs
Publication statusE-pub ahead of print - 24 Jul 2018

King's Authors

Abstract

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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