Changes of tRNA-Derived Fragments by Alzheimer’s Disease in Cerebrospinal Fluid and Blood Serum

Article type: Research Article

Authors: Wu, Wenzhe^a | Shen, Audrey^b | Lee, Inhan^c | Miranda-Morales, Ernesto G.^d | Spratt, Heidi^{e; f} | Pappolla, Miguel A.^d | Fang, Xiang^d | Bao, Xiaoyong^{a; e; f; g; *}

Affiliations: [a] Department of Pediatrics, The University of Texas Medical Branch, Galveston, TX, USA | [b] Department of Human Physiology, Boston University, Boston, MA, USA | [c] miRcore, Ann Arbor, MI, USA | [d] Department of Neurology and Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, TX, USA | [e] Department of Biostatistics and Data Science, The University of Texas Medical Branch, Galveston, TX, USA | [f] The Institute of Translational Sciences, The University of Texas Medical Branch, Galveston, TX, USA | [g] The Institute for Human Infections and Immunity, The University of Texas Medical Branch, Galveston, TX, USA

Correspondence: [*] Correspondence to: Xiaoyong Bao, PhD, Division of Clinical and Experimental Immunology & Infectious Diseases, Department of Pediatrics, 301 University Boulevard, Galveston, TX 77555-0372, USA. Tel.: +1 409 772 1777; Fax: +1 409 772 0460; E-mail: xibao@utmb.edu.

Abstract: Background:Alzheimer’s disease (AD) is the most common type of dementia, affecting individuals over 65. AD is also a multifactorial disease, with disease mechanisms incompletely characterized, and disease-modifying therapies are marginally effective. Biomarker signatures may shed light on the diagnosis, disease mechanisms, and the development of therapeutic targets. tRNA-derived RNA fragments (tRFs), a family of recently discovered small non-coding RNAs, have been found to be significantly enhanced in human AD hippocampus tissues. However, whether tRFs change in body fluids is unknown. Objective:To investigate whether tRFs in body fluids are impacted by AD. Methods:We first used T4 polynucleotide kinase-RNA-seq, a modified next-generation sequencing technique, to identify detectable tRFs in human cerebrospinal fluid and serum samples. The detectable tRFs were then compared in these fluids from control, AD, and mild cognitive impairment patients using tRF qRT-PCR. The stability of tRFs in serum was also investigated by checking the change in tRFs in response to protein digestion or exosome lysis. Results:Among various tRFs, tRF5-ProAGG seemed to be impacted by AD in both cerebrospinal fluid and serum. AD-impacted serum tRF5-ProAGG showed a correlation with the AD stage. Putative targets of tRF5-ProAGG in the hippocampus were also predicted by a computational algorithm, with some targets being validated experimentally and one of them being in a negative correlation with tRF5-ProAGG even using a small size of samples. Conclusions:tRF5-ProAGG showed the potential as an AD biomarker and may play a role in disease progression.

Keywords: Alzheimer’s disease, biomarker, cerebrospinal fluid, serum, tRNA-derived RNA fragments

DOI: 10.3233/JAD-230412

Journal: Journal of Alzheimer's Disease, vol. 96, no. 3, pp. 1285-1304, 2023