1. Human brain small extracellular vesicles contain selectively packaged, full-length mRNA.
- Author
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Ransom LS, Liu CS, Dunsmore E, Palmer CR, Nicodemus J, Ziomek D, Williams N, and Chun J
- Subjects
- Humans, Animals, Mice, Neurons metabolism, Astrocytes metabolism, Microglia metabolism, Transcriptome genetics, Mice, Inbred C57BL, Extracellular Vesicles metabolism, RNA, Messenger metabolism, RNA, Messenger genetics, Brain metabolism, Alzheimer Disease metabolism, Alzheimer Disease genetics, Alzheimer Disease pathology
- Abstract
Brain cells release and take up small extracellular vesicles (sEVs) containing bioactive nucleic acids. sEV exchange is hypothesized to contribute to stereotyped spread of neuropathological changes in the diseased brain. We assess mRNA from sEVs of postmortem brain from non-diseased (ND) individuals and those with Alzheimer's disease (AD) using short- and long-read sequencing. sEV transcriptomes are distinct from those of bulk tissue, showing enrichment for genes including mRNAs encoding ribosomal proteins and transposable elements such as human-specific LINE-1 (L1Hs). AD versus ND sEVs show enrichment of inflammation-related mRNAs and depletion of synaptic signaling mRNAs. sEV mRNAs from cultured murine primary neurons, astrocytes, or microglia show similarities to human brain sEVs and reveal cell-type-specific packaging. Approximately 80% of neural sEV transcripts sequenced using long-read sequencing are full length. Motif analyses of sEV-enriched isoforms elucidate RNA-binding proteins that may be associated with sEV loading. Collectively, we show that mRNA in brain sEVs is intact, selectively packaged, and altered in disease., Competing Interests: Declaration of interests J.C. has been or is a consultant or scientific advisory board member or has received research support for projects unrelated to the current work from the following: Aardvark Therapeutics, Aardwolf Therapeutics, Abbott/Abbvie, Amira Pharmaceuticals, Arena Pharmaceuticals, Autobahn Therapeutics, Biogen Idec, BrainStorm Cell Therapeutics, Bristol Myers Squibb, Celgene, GSK, Inception Sciences, Janssen Research and Development, Longboard Pharmaceuticals, MindX, Mitsubishi Tanabe, Neurocrine Biosciences, Novartis Pharmaceuticals, Ono Pharmaceuticals, Pfizer, Pipeline Therapeutics, RuiYi, ShouTi, Simulyve International, Structure Therapeutics, Taisho Pharmaceutical Co., Travecta Therapeutics, Trevena, and Vial. J.C. has an employment relationship with Neurocrine Biosciences, a company that may potentially benefit from the research results. J.C.’s relationship with Neurocrine Biosciences has been reviewed and approved by the Sanford Burnham Prebys Medical Discovery Institute in accordance with its conflict of interest policies., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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