Kristian Juul-Madsen, Ina-Maria Rudolph, Jemila P. Gomes, Katrina Meyer, Peter L. Ovesen, Malgorzata Gorniak-Walas, Marianna Kokoli, Narasimha S. Telugu, Malthe von Tangen Sivertsen, Fabia Febbraro, Duncan S. Sutherland, Johan Palmfeldt, Sebastian Diecke, Olav M. Andersen, Matthias Selbach, Thomas E. Willnow
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We studied SORLA<sup>N1358S</sup>, carrying a mutation in its ligand binding domain, to learn more about receptor functions relevant for human brain health.</p>\n </section>\n \n <section>\n \n <h3> METHODS</h3>\n \n <p>We investigated consequences of SORLA<sup>N1358S</sup> expression in induced pluripotent stem cell (iPSC)-derived human neurons and microglia, using unbiased proteome screens and functional cell assays.</p>\n </section>\n \n <section>\n \n <h3> RESULTS</h3>\n \n <p>We identified alterations in the SORLA<sup>N1358S</sup> interactome linked to biogenesis of exosomes. Consequently, the mutant receptor failed to promote release and neurotrophic qualities of exosomes, a defect attributed to altered exosomal content of microRNAs controlling neuronal maturation.</p>\n </section>\n \n <section>\n \n <h3> DISCUSSION</h3>\n \n <p>We identified a role for SORLA in controlling quantity and neurotrophic quality of exosomes secreted by cells, suggesting impaired cellular cross talk through exosomes as a pathological trait contributing to AD pathology in carriers of <i>SORL1</i> variants.</p>\n </section>\n \n <section>\n \n <h3> Highlights</h3>\n \n <div>\n <ul>\n \n <li>Familial Alzheimer's disease mutation in <i>SORL1</i> changes interactome of mutant Sortilin-related receptor with A-type repeats (SORLA).</li>\n \n <li>Mutant SORLA impairs release of exosomes from neurons and microglia.</li>\n \n <li>Mutant exosomes lack neurotrophic qualities.</li>\n \n <li>Defect linked to alterations in microRNA content.</li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 9","pages":""},"PeriodicalIF":11.1000,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://alz-journals.onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70591","citationCount":"0","resultStr":"{\"title\":\"Familial Alzheimer's disease mutation identifies novel role of SORLA in release of neurotrophic exosomes\",\"authors\":\"Kristian Juul-Madsen, Ina-Maria Rudolph, Jemila P. 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Familial Alzheimer's disease mutation identifies novel role of SORLA in release of neurotrophic exosomes
INTRODUCTION
Mutations in SORL1, encoding the sorting receptor Sortilin-related receptor with A-type repeats (SORLA), are found in individuals with Alzheimer's disease (AD). We studied SORLAN1358S, carrying a mutation in its ligand binding domain, to learn more about receptor functions relevant for human brain health.
METHODS
We investigated consequences of SORLAN1358S expression in induced pluripotent stem cell (iPSC)-derived human neurons and microglia, using unbiased proteome screens and functional cell assays.
RESULTS
We identified alterations in the SORLAN1358S interactome linked to biogenesis of exosomes. Consequently, the mutant receptor failed to promote release and neurotrophic qualities of exosomes, a defect attributed to altered exosomal content of microRNAs controlling neuronal maturation.
DISCUSSION
We identified a role for SORLA in controlling quantity and neurotrophic quality of exosomes secreted by cells, suggesting impaired cellular cross talk through exosomes as a pathological trait contributing to AD pathology in carriers of SORL1 variants.
Highlights
Familial Alzheimer's disease mutation in SORL1 changes interactome of mutant Sortilin-related receptor with A-type repeats (SORLA).
Mutant SORLA impairs release of exosomes from neurons and microglia.
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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