ApoE3 Christchurch and tau interaction as a protective mechanism against Alzheimer's disease

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dc.contributor.authorPerez-Corredor, Paula
dc.contributor.authorArevalo-Alquichire, Said
dc.contributor.authorMazzarino, Randall
dc.contributor.authorO'Hare, Michael
dc.contributor.authorMuriel-Torres, Andres
dc.contributor.authorVacano, Guido
dc.contributor.authorVanderleest, Timothy
dc.date.accessioned2026-04-04T13:37:45Z
dc.date.available2026-04-04T13:37:45Z
dc.date.issued2025
dc.departmentİnönü Üniversitesi
dc.description.abstractINTRODUCTION: We described a protected case with familial Alzheimer's disease, homozygous for apolipoprotein E3 (APOE3) Christchurch variant (ApoE3Ch), exhibiting low tau protein levels despite genetic predisposition to the disease due to presenilin (PSEN)1-E280A. 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-type and Christchurch variants to identify additional protective mechanisms of ApoE3Ch. METHODS: We performed pull-down of mouse brain lysates using His-tag-ApoE3 recombinant proteins and determined interacting partners of ApoE3 via mass-spectrometry. We then performed in vitro and in vivo assays to validate the top interactors. RESULTS: We found enhanced binding of ApoE3Ch to tau and Dickkopf-1 (Dkk1, a WNT/beta-catenin 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.
dc.description.sponsorshipRemondi Family Foundation; Edward N. & Della L. Thome Memorial Foundation; Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation
dc.description.sponsorshipSpecial thanks to Mr. John Remondi for suggesting the pursuit of studies examining the direct protective effects of ApoE Christchurch and to Ms. Melissa Paul for her stewardship in support of this research project. We thank Drs. Kiessling and Ortiz-Cordero for sharing some of the recombinant proteins. The authors also acknowledge R.A.O. for his invaluable contributions to this manuscript. Unfortunately, R.A.O. passed away in April 2025. We are grateful for the generous support from the Remondi Family Foundation. Additional funding was provided to J.F.A.-V. by the Edward N. & Della L. Thome Memorial Foundation and the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation. Both J.F.A.-V. and L.A.K. would like to acknowledge the contribution of Good Ventures for their substantial gifts supporting this work.
dc.identifier.doi10.1002/alz.70396
dc.identifier.issn1552-5260
dc.identifier.issn1552-5279
dc.identifier.issue7
dc.identifier.orcid0000-0002-3366-7384
dc.identifier.orcid0000-0002-2833-3697
dc.identifier.orcid0009-0004-5592-235X
dc.identifier.pmid40637118
dc.identifier.scopus2-s2.0-105010643397
dc.identifier.scopusqualityQ1
dc.identifier.urihttps://doi.org/10.1002/alz.70396
dc.identifier.urihttps://hdl.handle.net/11616/110014
dc.identifier.volume21
dc.identifier.wosWOS:001543967200047
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherWiley
dc.relation.ispartofAlzheimers & Dementia
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.snmzKA_WOS_20250329
dc.subjectAlzheimer's disease
dc.subjectApoE3 Christchurch
dc.subjectapolipoprotein E
dc.subjectDkk1
dc.subjectoligomerization
dc.subjecttau
dc.titleApoE3 Christchurch and tau interaction as a protective mechanism against Alzheimer's disease
dc.typeArticle

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