The Alzheimer's disease-associated complement receptor 1 variant confers risk by impacting glial phagocytosis

IF 13 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's & Dementia Pub Date : 2025-07-09 DOI:10.1002/alz.70458

Nikoleta Daskoulidou, Bethany Shaw, Wioleta Milena Zelek, Bryan Paul Morgan

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Abstract

INTRODUCTION

Genome-wide association studies have implicated complement in Alzheimer's disease (AD). The CR1*2 variant of complement receptor 1 (CR1; CD35), confers increased AD risk. We confirmed CR1 expression on glial cells; however, how CR1 variants influence AD risk remains unclear.

METHODS

Induced pluripotent stem cell-derived microglia and astrocytes were generated from donors homozygous for the common CR1 variants (CR1*1/CR1*1;CR1*2/CR1*2). CR1 expression was quantified and phagocytic activity assessed using diverse targets (Escherichia coli bioparticles, amyloid β aggregates, and synaptoneurosomes), with or without serum opsonization.

RESULTS

Expression of CR1*1 was significantly higher than CR1*2 on glial lines. Phagocytosis for all targets was markedly enhanced following serum opsonization, attenuated by Factor I-depletion, demonstrating CR1 requirement for C3b processing. CR1*2-expressing glia showed significantly enhanced phagocytosis of all opsonized targets compared to CR1*1-expressing cells.

DISCUSSION

CR1 is critical for glial phagocytosis of opsonized targets. CR1*2, despite lower expression, enhances glial phagocytosis, providing mechanistic explanation of increased AD risk.

Highlights

Induced pluripotent stem cell (iPSC)-derived glia from individuals expressing the Alzheimer's disease (AD) risk variant complement receptor (CR) 1*2 exhibit lower CR1 expression compared to those from donors expressing the non-risk form CR1*1.
The iPSC-derived glia from individuals expressing the AD risk variant CR1*2 exhibit enhanced phagocytic activity for opsonized bacterial particles, amyloid-β aggregates and human synaptoneurosomes compared to those from donors expressing the non-risk form CR1*1.
We suggest that expression of the CR1*2 variant confers risk of AD by enhancing the phagocytic capacity of glia for opsonized targets.

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阿尔茨海默病相关的补体受体1变异通过影响神经胶质吞噬而增加风险

全基因组关联研究表明补体与阿尔茨海默病（AD）有关。补体受体1 （CR1）的CR1*2变异；CD35)会增加AD的风险。我们证实了CR1在胶质细胞上的表达；然而，CR1变异如何影响AD风险仍不清楚。方法采用供体纯合子制备常见CR1变异（CR1*1/CR1*1;CR1*2/CR1*2）的诱导多能干细胞衍生小胶质细胞和星形胶质细胞。使用不同的靶标（大肠杆菌生物颗粒、β淀粉样蛋白聚集体和突触eurosomes）对CR1表达进行量化，并评估吞噬活性，无论是否进行血清调节。结果CR1*1在胶质细胞中的表达明显高于CR1*2。在血清调理后，所有靶点的吞噬能力都显著增强，但因因子i缺失而减弱，表明C3b加工需要CR1。与表达CR1*1的细胞相比，表达CR1*2的胶质细胞对所有磷酸化靶点的吞噬能力显著增强。CR1对活化靶标的胶质吞噬至关重要。CR1*2虽然表达较低，但可增强胶质细胞吞噬作用，为AD风险增加提供了机制解释。来自表达阿尔茨海默病（AD）风险变体补体受体（CR） 1*2的个体的诱导多能干细胞（iPSC）衍生胶质细胞的CR1表达低于来自表达非风险形式CR1*1的供体。来自表达AD风险变体CR1*2的个体的ipsc衍生胶质细胞与来自表达非风险变体CR1*1的供体相比，对活化的细菌颗粒、淀粉样蛋白-β聚集体和人突触eurosomes的吞噬活性增强。我们认为，CR1*2变体的表达通过增强胶质细胞对磷酸化靶标的吞噬能力来增加AD的风险。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.