Small RNA Profiles of Brain Tissue-Derived Extracellular Vesicles in Alzheimer’s Disease

Issue title: Omics Approaches in Alzheimer’s Disease Research

Guest editors: Sudeshna Das

Article type: Research Article

Authors: Huang, Yiyao^a | Driedonks, Tom A.P.^a | Cheng, Lesley^b | Turchinovich, Andrey^{c; d} | Pletnikova, Olga^{e; f} | Redding-Ochoa, Javier^e | Troncoso, Juan C.^{e; g} | Hill, Andrew F.^{b; h} | Mahairaki, Vasiliki^{i; j} | Zheng, Lei^k | Witwer, Kenneth W.^{a; i; j; *}

Affiliations: [a] Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA | [b] Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Australia | [c] Division of Cancer Genome Research, German Cancer Research Center (DKFZ), Heidelberg, Germany | [d] Heidelberg Biolabs GmbH, Heidelberg, Germany | [e] Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA | [f] Department of Pathology and Anatomical Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA | [g] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA | [h] Institute of Health and Sport, Victoria University, Melbourne, Australia | [i] Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA | [j] Richman Family Precision Medicine Center of Excellence in Alzheimer’s Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA | [k] Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China

Correspondence: [*] Correspondence to: Kenneth W. Witwer, Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Tel.: +1 410 955 9770; Fax: +1 410 955 9823; E-mail: [email protected].

Abstract: Background:Extracellular vesicles (EVs) and non-coding RNAs (ncRNAs) are emerging contributors to Alzheimer’s disease (AD) pathophysiology. Differential abundance of ncRNAs carried by EVs may provide valuable insights into underlying disease mechanisms. Brain tissue-derived EVs (bdEVs) are particularly relevant, as they may offer valuable insights about the tissue of origin. However, there is limited research on diverse ncRNA species in bdEVs in AD. Objective:This study explored whether the non-coding RNA composition of EVs isolated from post-mortem brain tissue is related to AD pathogenesis. Methods:bdEVs from age-matched late-stage AD patients (n = 23) and controls (n = 10) that had been separated and characterized in our previous study were used for RNA extraction, small RNA sequencing, and qPCR verification. Results:Significant differences of non-coding RNAs between AD and controls were found, especially for miRNAs and tRNAs. AD pathology-related miRNA and tRNA differences of bdEVs partially matched expression differences in source brain tissues. AD pathology had a more prominent association than biological sex with bdEV miRNA and tRNA components in late-stage AD brains. Conclusions:Our study provides further evidence that EV non-coding RNAs from human brain tissue, including but not limited to miRNAs, may be altered and contribute to AD pathogenesis.

Keywords: Alzheimer’s disease, brain, ectosomes, exosomes, extracellular vesicles, microvesicles, miRNAs, non-coding RNAs, RNA sequencing, tRNAs

DOI: 10.3233/JAD-230872

Journal: Journal of Alzheimer's Disease, vol. 99, no. s2, pp. S235-S248, 2024