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    ApoE3 Christchurch and tau interaction as a protective mechanism against Alzheimer's disease
    (Wiley, 2025) Perez-Corredor, Paula; Arevalo-Alquichire, Said; Mazzarino, Randall; O'Hare, Michael; Muriel-Torres, Andres; Vacano, Guido; Vanderleest, Timothy
    INTRODUCTION: 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.