{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T16:56:27Z","timestamp":1790873787869,"version":"4.1.0"},"reference-count":57,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T00:00:00Z","timestamp":1752105600000},"content-version":"vor","delay-in-days":9,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T00:00:00Z","timestamp":1751328000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100012394","name":"Robert J. Kleberg, Jr. and Helen C. 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We reported the loss of interaction between ApoE3Ch and heparan sulfate proteoglycans (HSPGs) as a critical protective pathway. Here, we characterized differential interacting partners for both wild\u2010type and Christchurch variants to identify additional protective mechanisms of ApoE3Ch.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>We performed pull\u2010down of mouse brain lysates using His\u2010tag\u2010ApoE3 recombinant proteins and determined interacting partners of ApoE3 via mass\u2010spectrometry. We then performed in vitro and in vivo assays to validate the top interactors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>We found enhanced binding of ApoE3Ch to tau and Dickkopf\u20101 (Dkk1, a WNT\/\u03b2\u2010catenin antagonist) that resulted in reduced tau aggregation in vitro. We demonstrated that ApoE3Ch interacts directly with Dkk1 and tau, reducing tau pathology. These findings supported the hypothesis of novel protective effects of direct ApoE3Ch interactions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>\u2060Apolipoprotein E3 (ApoE3) Christchurch variant (ApoE3Ch) exhibits different protein interaction profiles compared to wild\u2010type ApoE3, as revealed by proteomic analyses and pull\u2010down experiments.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>The ApoE3Ch variant alters the protein's interaction with tau, thus affecting its aggregation in a tau biosensor cell assay and the retina of microtubule\u2010associated protein tau (MAPT*P301S) transgenic mice.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\u2060Gene ontology and pathway analyses indicate that ApoE3Ch interactors are associated with brain\u2010related disorders and specific upstream regulators, including MAPT, a gene encoding for tau.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\u2060Protein\u2013protein interaction studies showed increased binding of ApoE3Ch to Dickkopf1 (Dkk1), a Wnt\/\u03b2\u2010catenin pathway antagonist, as compared to ApoE3WT, thus indicating that multiple protective mechanisms are regulated by the ApoE3Ch variant<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Our study uncovers a novel protective effect of the ApoE3Ch variant against tau pathology, thus proposing new insights into Alzheimer's disease mechanisms and potential therapeutic targets<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.70396","type":"journal-article","created":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T11:00:15Z","timestamp":1752145215000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["ApoE3 Christchurch and tau interaction as a protective mechanism against Alzheimer's disease"],"prefix":"10.1002","volume":"21","author":[{"given":"Paula","family":"Perez\u2010Corredor","sequence":"first","affiliation":[{"name":"Schepens Eye Research Institute of Mass Eye and Ear and Department of Ophthalmology Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Said","family":"Arevalo\u2010Alquichire","sequence":"additional","affiliation":[{"name":"Schepens Eye Research Institute of 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