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Disease-associated RNA and protein signatures in iPSC-derived microglia model of Alzheimer’s disease

ABSTRACT: Microglia, the primary immune cells of the brain, are essential for maintaining neural homeostasis. Dysfunction of microglia is strongly associated with neurodegenerative diseases, including Alzheimer’s disease (AD), yet the underlying molecular mechanisms remain incompletely understood. In this study, we compared microglia derived from induced pluripotent stem cells (iPSCs) of sporadic AD patients and healthy donors, identifying AD-associated alterations in mRNAs, proteins, and small non-coding RNAs (sncRNAs). Gene Ontology analysis of total RNA sequencing and proteomic data suggested significant dysregulation of pathways involved in extracellular communication, intracellular transport, cytoskeletal dynamics, and protein–protein interactions. Using a modified T4 PNK–sncRNA sequencing approach, we further identified disease-associated sncRNAs, including several previously uncharacterized species. Together, these findings highlight the utility of iPSC-derived microglia for modeling AD and uncover molecular alterations that may inform future therapeutic strategies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE332551 | GEO | 2026/06/18

REPOSITORIES: GEO

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Project description:The ongoing pandemic of coronavirus disease 2019 (COVID-19), which results from the rapid spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a significant global public health threat, with molecular mechanisms underlying its pathogenesis largely unknown. Small non-coding RNAs (sncRNAs) are known to play important roles in almost all biological processes. In the context of viral infections, sncRNAs have been shown to regulate the host responses, viral replication, and host-virus interaction. Compared with other subfamilies of sncRNAs, including microRNAs (miRNAs) and Piwi-interacting RNAs (piRNAs), tRNA-derived RNA fragments (tRFs) are relatively new and emerge as a significant regulator of host-virus interactions. Using T4 PNK‐RNA‐seq, a modified next‐generation sequencing (NGS), we recently found that nasopharyngeal swabs (NPS) samples from SARS-CoV-2 positive and negative subjects show a significant difference in sncRNA profiles. There are about 166 SARS-CoV- 2-impacted sncRNAs. Among them, tRFs are the most significantly affected and almost all impacted tRFs are derived from the 5’-end of tRNAs (tRF5). Using a modified qRT-PCR, which was recently developed to specifically quantify tRF5s by isolating the tRF signals from its corresponding parent tRNA signals, we validated that tRF5s derived from tRNA GluCTC (tRF5-GluCTC), LysCTT (tRF5-LysCTT), ValCAC (tRF5-ValCAC), CysGCA (tRF5-CysGCA) and GlnCTG (tRF5-GlnCTG) are enhanced in NPS samples of SARS-CoV2 patients and SARS-CoV2-infected airway epithelial cells. In addition to host-derived ncRNAs, we also identified several sncRNAs derived from the virus (svRNAs), among which a svRNA derived from CoV2 genomic site 346 to 382 (sv-CoV2-346) has the highest expression. The induction of both tRFs and sv-CoV2-346 has not been reported previously, as the lack of the 3’-OH ends of these sncRNAs prevents them to be detected by routine NGS. In summary, our studies demonstrated the involvement of tRFs in COVID-19 and revealed new CoV2 svRNAs.

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Disease-associated RNA and protein signatures in iPSC-derived microglia model of Alzheimer’s disease

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