Downregulation of Dickkopf-3, a Wnt antagonist elevated in Alzheimer’s disease, restores synapse integrity and memory in a disease mouse model

Martin Flores, Nuria, Podpolny, Marina, McLeod, Faye, Workman, Isaac, Crawford, Karen, Ivanov, Dobril ORCID: https://orcid.org/0000-0001-6271-6301, Leonenko, Ganna ORCID: https://orcid.org/0000-0001-8025-661X, Escott-Price, Valentina ORCID: https://orcid.org/0000-0003-1784-5483 and Salinas, Patricia C 2024. Downregulation of Dickkopf-3, a Wnt antagonist elevated in Alzheimer’s disease, restores synapse integrity and memory in a disease mouse model. eLife 12 , RP89453. 10.7554/elife.89453

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Abstract

Increasing evidence supports a role for deficient Wnt signaling in Alzheimer’s disease (AD). Studies reveal that the secreted Wnt antagonist Dickkopf-3 (DKK3) colocalizes to amyloid plaques in AD patients. Here, we investigate the contribution of DKK3 to synapse integrity in healthy and AD brains. Our findings show that DKK3 expression is upregulated in the brains of AD subjects and that DKK3 protein levels increase at early stages in the disease. In hAPP-J20 and hAPPNL-G-F/NL-G-F mouse AD models, extracellular DKK3 levels are increased and DKK3 accumulates at dystrophic neuronal processes around plaques. Functionally, DKK3 triggers the loss of excitatory synapses through blockade of the Wnt/GSK3β signaling with a concomitant increase in inhibitory synapses via activation of the Wnt/JNK pathway. In contrast, DKK3 knockdown restores synapse number and memory in hAPP-J20 mice. Collectively, our findings identify DKK3 as a novel driver of synaptic defects and memory impairment in AD.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Advanced Research Computing @ Cardiff (ARCCA) Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/
Publisher:	eLife Sciences Publications
ISSN:	2050-084X
Date of First Compliant Deposit:	30 January 2024
Last Modified:	10 Jun 2024 08:18
URI:	https://orca.cardiff.ac.uk/id/eprint/165924

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