Your new experience awaits. Try the new design now and help us make it even better

ORIGINAL RESEARCH article

Front. Immunol.

Sec. Multiple Sclerosis and Neuroimmunology

This article is part of the Research TopicExploring miRNA Roles in Neuroinflammation and Brain Aging: Mechanisms and Therapeutic PotentialView all 4 articles

MiR-34a deficiency enhances nucleic acid sensing and type I IFN signaling in a mouse model of Alzheimer's disease

Provisionally accepted
Junling YangJunling Yang1*George Elliot TsourdinisGeorge Elliot Tsourdinis1,2Charlotte HolasCharlotte Holas1Mark Maienschein-ClineMark Maienschein-Cline3Robert LalondeRobert Lalonde4Ken-ichiro FukuchiKen-ichiro Fukuchi1*
  • 1University of Illinois Chicago College of Medicine at Peoria, Peoria, United States
  • 2Endeavor Health Cardiovascular Institute, University of Chicago, Chicago, United States
  • 3Research Informatics Core, Research Resources Center, University of Illinois Chicago, Chicago, United States
  • 4Université de Lorraine, Laboratoire Stress, Immunité, Pathogènes (UR SIMPA), Vandœuvre-les-Nancy, France

The final, formatted version of the article will be published soon.

Select one of your emails

You have multiple emails registered with Frontiers:

Notify me on publication

Please enter your email address:

If you already have an account, please login

You don't have a Frontiers account ? You can register here

MiR-34a is implicated in aging, cell senescence, inflammation, and neurodegenerative diseases. In order to investigate the role of miR-34a in Alzheimer’s disease (AD), we produced an AD mouse model, Tg-SwDI mice, with whole body/constitutive miR-34a knockout (KO). MiR-34a KO improved long-term memory in Tg-SwDI mice, which was associated with decreases in the ratio of insoluble Aβ42 to Aβ40 and with increases in soluble and insoluble Aβ40 in the cerebral cortex. Anti-Iba1 immunofluorescence revealed increases in activated microglia. Bulk RNA-sequencing of the hippocampus followed by a gene set enrichment analysis (Enrichr) identified “cellular response to type I interferon” and “type I interferon signaling pathway” as the most prominent gene sets in miR-34a KO Tg-SwDI mice compared to miR-34a wild-type Tg-SwDI mice. Many interferon-stimulated genes (ISGs) that characterize interferon responsive microglia (IRM) were upregulated in miR-34a KO Tg-SwDI mice. MiR-34a knockdown strongly enhanced ISGs expression in TLR7 ligand-stimulated BV2 and primary microglia. These results suggest that miR-34a inhibits the transition of microglia to the IRM state that may modulate synaptic and cognitive functions in neurodegenerative diseases and aging.

Keywords: Alzheimer's, Microglia, MicroRNA-34a, Neuroinflammation, type I interferon

Received: 28 Aug 2025; Accepted: 06 Feb 2026.

Copyright: © 2026 Yang, Tsourdinis, Holas, Maienschein-Cline, Lalonde and Fukuchi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Junling Yang
Ken-ichiro Fukuchi

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Supplementary Material