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6d ago

Alzheimer’s Study Ties Familial SORL1 Variant to Fewer, Weaker Brain Exosomes

Lab-grown human brain cells carrying SORLA N1358S shed fewer, less neurotrophic exosomes, implicating altered exosomal microRNAs.

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What Kristian Juul-Madsen and his research colleagues have now discovered is that if the SORLA-protein is defective, the brain cells become significantly worse at producing exosomes. Credit: Neuroscience News
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Overview

  • The peer-reviewed study in Alzheimer's & Dementia analyzes the SORLA N1358S variant linked to familial Alzheimer’s using human iPSC-derived models.
  • Cells with the mutation released about 30% fewer exosomes, and the vesicles were up to 50% less effective at supporting neighboring cell growth and maturation.
  • Defects were observed in both neurons and microglia, indicating a broader role for SORLA in exosome formation across brain cell types.
  • Proteomic and RNA profiling tied the mutation to changes in the receptor’s interactome involved in exosome biogenesis and to shifts in exosomal microRNA and RNA-binding protein content.
  • Researchers highlight exploratory therapeutic directions to restore SORLA function or enhance exosome output, noting the findings are preclinical and require in vivo validation.