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

IF 13 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's & Dementia Pub Date : 2025-07-10 DOI:10.1002/alz.70396

Paula Perez-Corredor, Said Arevalo-Alquichire, Randall C. Mazzarino, Michael O'Hare, Andres F. Muriel-Torres, Guido N. Vacano, Timothy E. Vanderleest, William P. Miller, Lina Pineda-Lopez, Shivani Patel, Robert A. Obar, Nihat Polat, Leo A. Kim, Joseph F. Arboleda-Velasquez, Claudia Marino

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引用次数: 0

Abstract

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/β-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.

Highlights

⁠Apolipoprotein E3 (ApoE3) Christchurch variant (ApoE3Ch) exhibits different protein interaction profiles compared to wild-type ApoE3, as revealed by proteomic analyses and pull-down experiments.
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-associated protein tau (MAPT*P301S) transgenic mice.
⁠Gene ontology and pathway analyses indicate that ApoE3Ch interactors are associated with brain-related disorders and specific upstream regulators, including MAPT, a gene encoding for tau.
⁠Protein–protein interaction studies showed increased binding of ApoE3Ch to Dickkopf1 (Dkk1), a Wnt/β-catenin pathway antagonist, as compared to ApoE3WT, thus indicating that multiple protective mechanisms are regulated by the ApoE3Ch variant
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

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ApoE3 Christchurch和tau相互作用作为抗阿尔茨海默病的保护机制

我们描述了一个受保护的家族性阿尔茨海默病病例，载脂蛋白E3 （APOE3）基督城变体（ApoE3Ch）纯合子，尽管早老素（PSEN）1-E280A导致该疾病的遗传易感性，但仍表现出低tau蛋白水平。我们报道了ApoE3Ch和硫酸肝素蛋白聚糖（HSPGs）之间作为关键保护途径的相互作用的丧失。在这里，我们描述了野生型和基督城变体的不同相互作用伙伴，以确定ApoE3Ch的额外保护机制。方法利用His-tag-ApoE3重组蛋白对小鼠脑裂解物进行拉下分析，并通过质谱法确定ApoE3的相互作用伙伴。然后，我们进行了体外和体内试验来验证顶部相互作用物。结果我们发现ApoE3Ch与tau和Dickkopf-1 （Dkk1，一种WNT/β-catenin拮抗剂）的结合增强，导致体外tau聚集减少。我们证明ApoE3Ch直接与Dkk1和tau相互作用，减少tau病理。这些发现支持了ApoE3Ch直接相互作用的新型保护作用的假设。蛋白质组学分析和下拉实验显示，载脂蛋白E3 (ApoE3) Christchurch variant （ApoE3Ch）与野生型ApoE3表现出不同的蛋白质相互作用谱。ApoE3Ch变异改变了该蛋白与tau蛋白的相互作用，从而影响其在tau生物传感器细胞试验中的聚集和微管相关蛋白tau （MAPT*P301S）转基因小鼠的视网膜。基因本体论和通路分析表明，ApoE3Ch相互作用因子与脑相关疾病和特定的上游调节因子（包括编码tau的基因MAPT）有关。蛋白质-蛋白质相互作用研究表明，与ApoE3WT相比，ApoE3Ch与Wnt/β-catenin通路拮抗剂Dickkopf1 （Dkk1）的结合增加，从而表明ApoE3Ch变体可调节多种保护机制。我们的研究揭示了ApoE3Ch变体对tau病理的新保护作用，从而为阿尔茨海默病的机制和潜在的治疗靶点提供了新的见解

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来源期刊

Alzheimer's & Dementia 医学-临床神经学

CiteScore

14.50

自引率

5.00%

发文量

299

审稿时长

3 months

期刊介绍： Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.