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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Microglia engulf pathological proteins, but how they endocytose tau is unknown.</p>\n </section>\n \n <section>\n \n <h3> METHODS</h3>\n \n <p>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).</p>\n </section>\n \n <section>\n \n <h3> RESULTS</h3>\n \n <p>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.</p>\n </section>\n \n <section>\n \n <h3> DISCUSSION</h3>\n \n <p>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.</p>\n </section>\n \n <section>\n \n <h3> Highlights</h3>\n \n <div>\n <ul>\n \n <li>Microglial endocytosis of tau monomers and fibrils is dynamin-dependent.</li>\n \n <li>HSPG antagonism blocks microglial uptake of tau fibrils but not monomers.</li>\n \n <li>LRP1 antagonism or knockdown inconsistently inhibits tau uptake.</li>\n \n <li>TAT-Cre stimulates semi-selective uptake of fibrils over monomers.</li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 2","pages":""},"PeriodicalIF":13.0000,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.14418","citationCount":"0","resultStr":"{\"title\":\"Microglia internalize tau monomers and fibrils using distinct receptors but similar mechanisms\",\"authors\":\"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\",\"doi\":\"10.1002/alz.14418\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> INTRODUCTION</h3>\\n \\n <p>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.</p>\\n </section>\\n \\n <section>\\n \\n <h3> METHODS</h3>\\n \\n <p>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).</p>\\n </section>\\n \\n <section>\\n \\n <h3> RESULTS</h3>\\n \\n <p>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.</p>\\n </section>\\n \\n <section>\\n \\n <h3> DISCUSSION</h3>\\n \\n <p>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.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Highlights</h3>\\n \\n <div>\\n <ul>\\n \\n <li>Microglial endocytosis of tau monomers and fibrils is dynamin-dependent.</li>\\n \\n <li>HSPG antagonism blocks microglial uptake of tau fibrils but not monomers.</li>\\n \\n <li>LRP1 antagonism or knockdown inconsistently inhibits tau uptake.</li>\\n \\n <li>TAT-Cre stimulates semi-selective uptake of fibrils over monomers.</li>\\n </ul>\\n </div>\\n </section>\\n </div>\",\"PeriodicalId\":7471,\"journal\":{\"name\":\"Alzheimer's & Dementia\",\"volume\":\"21 2\",\"pages\":\"\"},\"PeriodicalIF\":13.0000,\"publicationDate\":\"2024-12-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.14418\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Alzheimer's & Dementia\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/alz.14418\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Alzheimer's & Dementia","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/alz.14418","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
Microglia internalize tau monomers and fibrils using distinct receptors but similar mechanisms
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.
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.
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