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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 hAPP\n                    <jats:sup>NL-G-F\/NL-G-F<\/jats:sup>\n                    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\/GSK3\u03b2 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.\n                  <\/jats:p>","DOI":"10.7554\/elife.89453","type":"journal-article","created":{"date-parts":[[2023,9,25]],"date-time":"2023-09-25T11:34:10Z","timestamp":1695641650000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.89453","source":"Crossref","is-referenced-by-count":12,"title":["Downregulation of Dickkopf-3, a Wnt antagonist elevated in Alzheimer\u2019s disease, restores synapse integrity and memory in a disease mouse model"],"prefix":"10.7554","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2537-751X","authenticated-orcid":true,"given":"Nuria","family":"Martin Flores","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02jx3x895","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Cell and Developmental Biology, Division of Biosciences, University College London","place":["London, United 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