Protective mechanisms against Alzheimer's disease in APOE3-Christchurch homozygous astrocytes

IF 11.1 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's & Dementia Pub Date : 2025-09-18 DOI:10.1002/alz.70589

Xinran Tian, Erica Keane Rivera, Inyoung Hwang, Arina A. Nikitina, Jennifer A. Smith, Youngsuh J. Cho, Julia Sala-Jarque, Austin DuBose, Clare Andriola, Toby Gollan-Myers, Kenneth S. Kosik

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Abstract

INTRODUCTION

Alzheimer's disease (AD) is characterized by tau pathology, leading to neurodegeneration. Astrocytes regulate central nervous system homeostasis and influence AD progression. The APOE3-Christchurch (APOE3-Ch) variant is linked to AD resilience, but its protective mechanisms remain unclear.

METHODS

Human induced pluripotent stem cell–derived astrocytes (APOE3-Ch and wild type) were used to assess tau uptake, clearance, lipid metabolism, and transcriptomic adaptations. Fluorescently labeled 2N4R-P301L tau oligomers were tracked, and pathway-specific inhibitors dissected tau clearance mechanisms. Lipidomic and transcriptomic analyses were performed to identify genotype-specific adaptations.

RESULTS

APOE3-Ch astrocytes exhibited enhanced tau uptake via heparan sulfate proteoglycan- and lipoprotein receptor-related protein 1-mediated pathways and superior clearance through lysosomal and proteasomal degradation. They exported less tau, limiting propagation. Transcriptomic analyses revealed upregulation of genes involved in cell projection assembly and endocytosis. Lipidomic profiling showed reduced ceramides and gamma-linolenic acid, linked to decreased neuroinflammation and ferroptosis.

DISCUSSION

APOE3-Ch astrocytes promote tau clearance and metabolic adaptations, providing insights into genetic resilience in AD and potential therapeutic targets.

Highlights

APOE3-Christchurch (APOE3-Ch) astrocytes exhibit significantly increased tau internalization compared to wild-type astrocytes, facilitated by upregulated heparan sulfate proteoglycan and low-density lipoprotein receptor-related protein 1 pathways.
APOE3-Ch astrocytes demonstrate more efficient tau degradation via both lysosomal and proteasomal pathways, while exporting significantly less tau, potentially reducing tau propagation in the central nervous system.
APOE3-Ch astrocytes show upregulation of genes involved in cell projection assembly and endocytosis, suggesting structural and functional modifications that enhance tau processing.
Lipidomic profiling reveals reduced ceramide levels and gamma-linolenic acid downregulation in APOE3-Ch astrocytes, alterations linked to reduced neuroinflammatory and ferroptotic activity, contributing to the protective phenotype.

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APOE3-Christchurch纯合子星形细胞抗阿尔茨海默病的保护机制。

阿尔茨海默病（AD）以tau蛋白病理为特征，导致神经退行性变。星形胶质细胞调节中枢神经系统稳态并影响AD的进展。APOE3-Christchurch （APOE3-Ch）变体与AD恢复能力有关，但其保护机制尚不清楚。方法：使用人诱导多能干细胞来源的星形胶质细胞（APOE3-Ch和野生型）来评估tau摄取、清除、脂质代谢和转录组适应。荧光标记的2N4R-P301L tau低聚物被跟踪，途径特异性抑制剂剖析了tau清除机制。脂质组学和转录组学分析鉴定基因型特异性适应。结果：APOE3-Ch星形胶质细胞通过硫酸肝素蛋白多糖和脂蛋白受体相关蛋白1介导的途径增强了tau蛋白的摄取，并通过溶酶体和蛋白酶体降解增强了tau蛋白的清除。它们输出的tau较少，限制了繁殖。转录组学分析显示，参与细胞投射组装和内吞作用的基因上调。脂质组学分析显示神经酰胺和γ -亚麻酸的减少与神经炎症和铁下垂的减少有关。讨论：APOE3-Ch星形胶质细胞促进tau清除和代谢适应，为AD的遗传弹性和潜在的治疗靶点提供了见解。与野生型星形胶质细胞相比，APOE3-Christchurch （APOE3-Ch）星形胶质细胞表现出明显增加的tau内化，这是由硫酸肝素蛋白聚糖和低密度脂蛋白受体相关蛋白1途径的上调促进的。APOE3-Ch星形胶质细胞通过溶酶体和蛋白酶体途径显示出更有效的tau降解，同时输出的tau显著减少，可能减少tau在中枢神经系统中的繁殖。APOE3-Ch星形胶质细胞显示参与细胞投射组装和内吞作用的基因上调，表明结构和功能的改变增强了tau加工。脂质组学分析显示APOE3-Ch星形胶质细胞中神经酰胺水平降低和γ -亚麻酸下调，这种改变与神经炎症和铁细胞活性降低有关，有助于保护表型。

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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.