UC San Diego

Cells in the brain can communicate via the exchange of extracellular vesicles (EV) carrying bioactive proteins and nucleic acids. A subset of EVs called exosomes are ~30-150nm in diameter and generated by the endocytic pathway and are described as small EVs (sEVs) when isolated experimentally. I prepared sEVs from non-diseased (ND) and Alzheimer’s disease (AD) human postmortem brain tissue samples and sequenced their mRNA contents. Short-read sequencing revealed that mRNAs in sEVs were differentially expressed relative to associated bulk tissue and across disease states. Cell-type specific expression was observed in sEVs from murine primary neurons, astrocytes, and microglia, and mRNAs enriched in sEVs relative to source cells showed concordance with mRNAs enriched in human brain sEVs. Long-read sequencing of human brain sEVs identified over 10,000 full-length transcripts and enabled the identification of common sequence motifs in sEV-enriched mRNAs. In light of recent reports of virus-like properties in some brain sEVs, and inspired by our observation of retrotransposon mRNAs that were highly enriched in brain sEVs, we also developed a culture model of retro-insertion of sEV mRNAs. Collectively, this dissertation unveils a previously underappreciated landscape of selectively-packaged, intact mRNAs in brain sEVs, and explores the potential for retrovirus-like genomic insertion of sEV mRNAs.