Microglia internalize tau monomers and fibrils using distinct receptors but similar mechanisms

IF 13 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's & Dementia Pub Date : 2024-12-23 DOI:10.1002/alz.14418

Kristian F. Falkon, Liliana Danford, Eduardo Gutierrez Kuri, Paulina Esquinca-Moreno, Yaren L. Peña Señeriz, Sabrina Smith, Jessica L. Wickline, Ariel Louwrier, Jacob A. McPhail, Naomi L. Sayre, Sarah C. Hopp

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引用次数: 0

Abstract

INTRODUCTION

Alzheimer's disease (AD) and other tauopathies are characterized by intracellular aggregates of microtubule-associated protein tau that are actively released and promote proteopathic spread. Microglia engulf pathological proteins, but how they endocytose tau is unknown.

METHODS

We measured endocytosis of different tau species by microglia after pharmacological modulation of macropinocytosis or clathrin-mediated endocytosis (CME) or antagonism/genetic depletion of known tau receptors heparan-sulfate proteoglycans (HSPGs) and low-density lipoprotein receptor-related protein 1 (LRP1).

RESULTS

Dynamin inhibition decreased microglial endocytosis of all tested tau species. Meanwhile, HSPG antagonism blocked only fibril uptake, and LRP1 antagonism or genetic depletion inconsistently inhibited the endocytosis of fibrils and monomers. Cre recombinase robustly enhanced tau uptake with partial selectivity for fibrils.

DISCUSSION

These data show that microglia take up both tau monomers and aggregates via a dynamin-dependent form of endocytosis (eg, CME) but may differ in using HSPGs for entry depending on species.

Highlights

Microglial endocytosis of tau monomers and fibrils is dynamin-dependent.
HSPG antagonism blocks microglial uptake of tau fibrils but not monomers.
LRP1 antagonism or knockdown inconsistently inhibits tau uptake.
TAT-Cre stimulates semi-selective uptake of fibrils over monomers.

Abstract Image

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小胶质细胞利用不同的受体内化tau单体和原纤维，但机制相似

阿尔茨海默病（AD）和其他tau病变的特征是微管相关蛋白tau在细胞内聚集，其被积极释放并促进蛋白质病变扩散。小胶质细胞吞噬病理蛋白，但它们如何内吞tau蛋白尚不清楚。方法：通过药理调节巨噬细胞作用或网格蛋白介导的内吞作用（CME）或已知tau受体硫酸肝素蛋白聚糖（HSPGs）和低密度脂蛋白受体相关蛋白1 （LRP1）的拮抗/遗传耗竭，我们测量了小胶质细胞对不同tau物种的内吞作用。结果动力蛋白抑制降低了所有tau蛋白的小胶质细胞内吞作用。同时，HSPG拮抗剂仅阻断原纤维摄取，LRP1拮抗剂或基因缺失不一致地抑制原纤维和单体的内吞作用。Cre重组酶对原纤维的部分选择性增强了tau蛋白的摄取。这些数据表明，小胶质细胞通过动力蛋白依赖形式的内吞作用（如CME）摄取tau单体和聚集体，但根据物种的不同，使用hspg进入可能有所不同。小胶质细胞内吞tau单体和原纤维是动力蛋白依赖性的。HSPG拮抗剂阻断小胶质细胞摄取tau原纤维，但不阻断单体。LRP1拮抗或敲低不一致地抑制tau摄取。TAT - Cre刺激原纤维对单体的半选择性摄取。

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.