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Reversal of Synapse Degeneration by Restoring Wnt Signaling in the Adult Hippocampus

Marzo, A; Galli, S; Lopes, D; McLeod, F; Podpolny, M; Segovia-Roldan, M; Ciani, L; ... Salinas, PC; + view all (2016) Reversal of Synapse Degeneration by Restoring Wnt Signaling in the Adult Hippocampus. Current Biology , 26 (19) pp. 2551-2561. 10.1016/j.cub.2016.07.024. Green open access

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Abstract

Synapse degeneration occurs early in neurodegenerative diseases and correlates strongly with cognitive decline in Alzheimer’s disease (AD). The molecular mechanisms that trigger synapse vulnerability and those that promote synapse regeneration after substantial synaptic failure remain poorly understood. Increasing evidence suggests a link between a deficiency in Wnt signaling and AD. The secreted Wnt antagonist Dickkopf-1 (Dkk1), which is elevated in AD, contributes to amyloid-β-mediated synaptic failure. However, the impact of Dkk1 at the circuit level and the mechanism by which synapses disassemble have not yet been explored. Using a transgenic mouse model that inducibly expresses Dkk1 in the hippocampus, we demonstrate that Dkk1 triggers synapse loss, impairs long-term potentiation, enhances long-term depression, and induces learning and memory deficits. We decipher the mechanism involved in synapse loss induced by Dkk1 as it can be prevented by combined inhibition of the Gsk3 and RhoA-Rock pathways. Notably, after loss of synaptic connectivity, reactivation of the Wnt pathway by cessation of Dkk1 expression completely restores synapse number, synaptic plasticity, and long-term memory. These findings demonstrate the remarkable capacity of adult neurons to regenerate functional circuits and highlight Wnt signaling as a targetable pathway for neuronal circuit recovery after synapse degeneration.

Type: Article
Title: Reversal of Synapse Degeneration by Restoring Wnt Signaling in the Adult Hippocampus
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.cub.2016.07.024
Publisher version: http://dx.doi.org/10.1016/j.cub.2016.07.024
Language: English
Additional information: © 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Cell Biology, LONG-TERM DEPRESSION, TRANSGENIC MOUSE MODELS, AMYLOID-BETA PROTEIN, ALZHEIMERS-DISEASE, DENDRITIC SPINE, SPATIAL MEMORY, NEGATIVE MODULATOR, WNT/BETA-CATENIN, RAT HIPPOCAMPUS, GENE-EXPRESSION
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases > MRC Prion Unit at UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: http://discovery.ucl.ac.uk/id/eprint/1514846
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