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Transl Psychiatry. 2018 Sep 20;8(1):179. doi: 10.1038/s41398-018-0231-6.

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

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Maurice Wohl Clinical Neuroscience Institute, King's College London, 5 Cutcombe Road, London, SE5 9RT, UK.
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Investigación Sanitaria La Paz (IdiPaz), Autonomous University of Madrid (UAM), Madrid, Spain.
Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, OX3 7JX, UK.
Boston University School of Medicine, Boston, MA, USA.
Department of Veterans Affairs, Geriatric Research Education and Clinical Center, Bedford, MA, USA.
Institute of Cardiovascular and Medical Science, University of Glasgow, Glasgow, G12 8QQ, Scotland.
Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Royal Free Campus, University College London, Rowland Hill Street, London, NW3 2PF, UK.
University of Exeter Medical School, Exeter, UK.
Maurice Wohl Clinical Neuroscience Institute, King's College London, 5 Cutcombe Road, London, SE5 9RT, UK.


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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