Long RNA Profiles of Human Brain Extracellular Vesicles Provide New Insights into the Pathogenesis of Alzheimer's Disease

Alzheimer's disease (AD) is the most common neurodegenerative disorder. Extracellular vesicles (EVs), carriers of nucleic acids, lipids, and proteins, are known to play significant roles in neurodegenerative pathogenesis. Studies have shown that EVs from AD human brain tissue contain toxic proteins that may lead to neuron cell damage and loss. However, the potential contribution of EV long RNAs (exLR) to AD pathobiology is less well known, and their biochemical functions and molecular properties remain obscure. Here, EVs were isolated from the frontal cortex of normal control (NC; N = 10) and AD (N = 8) brain tissue donors. We performed exLR profiling on the isolated EVs followed by pathway analysis and weighted gene co- expression network analysis (WGCNA). A total of 1012 mRNAs, 320 long non-coding RNAs (lncRNAs), and 119 circular RNAs (circRNAs) were found to be differentially expressed (DE) in AD-EVs compared with NC-EVs. Functional analysis of the DEmRNAs revealed that metal ion transport, calcium signaling, and various neuronal processes were enriched. To investigate the possible functions of the identified DElncRNAs and DEcircRNAs, competing endogenous RNA (ceRNA) networks were constructed and subjected to WGCNA, in which two gene modules were identified to be significantly correlated with AD. Moreover, we discovered that NC-EVs were more effective than AD-EVs in promoting cytokine expression, phagocytosis, and induction of calcium signaling in microglia. Our study provides an in- depth characterization of brain tissue exLR and identifies several RNAs that correlate with the pathogenesis of AD.