Human brain small extracellular vesicles contain selectively packaged, full-length mRNA
Linnea S. Ransom,
Christine S. Liu,
Emily Dunsmore,
Carter R. Palmer,
Juliet Nicodemus,
Derya Ziomek,
Nyssa Williams,
Jerold Chun
Affiliations
Linnea S. Ransom
Biomedical Sciences Graduate Program, School of Medicine, University of California, San Diego, La Jolla, CA, USA; Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
Christine S. Liu
Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
Emily Dunsmore
Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
Carter R. Palmer
Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
Juliet Nicodemus
Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
Derya Ziomek
Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
Nyssa Williams
Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
Jerold Chun
Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA; Corresponding author
Summary: 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.
