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

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          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 (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 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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          Most cited references 38

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          LDL-receptor-related proteins in Wnt signal transduction.

          The Wnt family of secreted signalling molecules are essential in embryo development and tumour formation. The Frizzled (Fz) family of serpentine receptors function as Wnt receptors, but how Fz proteins transduce signalling is not understood. In Drosophila, arrow phenocopies the wingless (DWnt-1) phenotype, and encodes a transmembrane protein that is homologous to two members of the mammalian low-density lipoprotein receptor (LDLR)-related protein (LRP) family, LRP5 and LRP6 (refs 12-15). Here we report that LRP6 functions as a co-receptor for Wnt signal transduction. In Xenopus embryos, LRP6 activated Wnt-Fz signalling, and induced Wnt responsive genes, dorsal axis duplication and neural crest formation. An LRP6 mutant lacking the carboxyl intracellular domain blocked signalling by Wnt or Wnt-Fz, but not by Dishevelled or beta-catenin, and inhibited neural crest development. The extracellular domain of LRP6 bound Wnt-1 and associated with Fz in a Wnt-dependent manner. Our results indicate that LRP6 may be a component of the Wnt receptor complex.
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            Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment.

            To evaluate the total number of synapses in the stratum radiatum (str rad) of the human hippocampal CA1 subfield in individuals with mild Alzheimer disease (mAD), mild cognitive impairment (MCI), or no cognitive impairment (NCI) and determine if synapse loss is an early event in the progression of the disease. Short postmortem autopsy tissue was obtained, and an unbiased stereologic sampling scheme coupled with transmission electron microscopy was used to directly visualize synaptic contacts. Individuals with mAD had fewer synapses (55%) than the other two diagnostic groups. Individuals with MCI had a mean synaptic value that was 18% lower than the NCI group mean. The total number of synapses showed a correlation with several cognitive tests including those involving both immediate and delayed recall. Total synaptic numbers showed no relationship to the subject's Braak stage or to APOE genotype. The volume of the str rad was reduced in mAD vs the other two diagnostic groups that were not different from each other. These results strongly support the concept that synapse loss is a structural correlate involved very early in cognitive decline in mild Alzheimer disease (mAD) and supports mild cognitive impairment as a transitional stage between mAD and no cognitive impairment.
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              Early-onset Alzheimer's disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene.

               L Fidani,  M Härlin,  A Goate (1991)
              A mutation at codon 717 of the beta-amyloid precursor protein gene has been found to cosegregate with familial Alzheimer's disease in a single family. This mutation has been reported in a further five out of approximately 100 families multiply affected by Alzheimer's disease. We have identified another family, F19, in which we have detected linkage between the beta-amyloid precursor protein gene and Alzheimer's disease. Direct sequencing of exon 17 in affected individuals from this family has revealed a base change producing a Val----Gly substitution, also at codon 717. The occurrence of a second allelic variant at codon 717 linked to the Alzheimer's phenotype supports the hypothesis that they are pathogenic mutations.
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                Author and article information

                Contributors
                Richard.1.Killick@kcl.ac.uk
                Journal
                Transl Psychiatry
                Transl Psychiatry
                Translational Psychiatry
                Nature Publishing Group UK (London )
                2158-3188
                20 September 2018
                20 September 2018
                2018
                : 8
                Affiliations
                [1 ]ISNI 0000 0001 2322 6764, GRID grid.13097.3c, Maurice Wohl Clinical Neuroscience Institute, , King’s College London, ; 5 Cutcombe Road, London, SE5 9RT UK
                [2 ]ISNI 0000000119578126, GRID grid.5515.4, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Investigación Sanitaria La Paz (IdiPaz), , Autonomous University of Madrid (UAM), ; Madrid, Spain
                [3 ]ISNI 0000 0004 1936 8948, GRID grid.4991.5, Department of Psychiatry, Warneford Hospital, , University of Oxford, ; Oxford, OX3 7JX UK
                [4 ]ISNI 0000 0004 0367 5222, GRID grid.475010.7, Boston University School of Medicine, ; Boston, MA USA
                [5 ]Department of Veterans Affairs, Geriatric Research Education and Clinical Center, Bedford, MA USA
                [6 ]ISNI 0000 0001 2193 314X, GRID grid.8756.c, Institute of Cardiovascular and Medical Science, , University of Glasgow, ; Glasgow, G12 8QQ Scotland
                [7 ]ISNI 0000000121901201, GRID grid.83440.3b, Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Royal Free Campus, , University College London, ; Rowland Hill Street, London, NW3 2PF UK
                [8 ]ISNI 0000 0004 1936 8024, GRID grid.8391.3, University of Exeter Medical School, ; Exeter, UK
                Article
                231
                10.1038/s41398-018-0231-6
                6145937
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: FundRef https://doi.org/10.13039/501100000265, Medical Research Council (MRC);
                Award ID: MR/M013944/1
                Award Recipient :
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                Article
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                © The Author(s) 2018

                Clinical Psychology & Psychiatry

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