# MicroRNA-29a-5p contributes to neuroinflammation through TLR7

## TL;DR

This study shows that miR-29a-5p, a microRNA linked to Alzheimer's disease, activates TLR7 in microglia, leading to neuroinflammation and neuronal injury.

## Contribution

The study identifies miR-29a-5p as a TLR7 agonist that directly contributes to neuroinflammation and alters microglial signaling in Alzheimer's disease.

## Key findings

- Extracellular miR-29a-5p activates TLR7 in microglia, inducing cytokine release and neuronal injury.
- miR-29a-5p injection in mice leads to microglial accumulation and neuronal damage via TLR7.
- RNAseq analysis shows downregulation of MAPK pathways in miR-29a-5p-treated mouse brains.

## Abstract

MicroRNAs (miRNAs) canonically regulate post-transcriptional gene expression, but they can also serve as ligands for Toll-like receptors (TLRs). These receptors and their associated signalling pathways contribute to inflammatory responses involved in various central nervous system (CNS) diseases, including Alzheimer’s disease (AD). Here, we investigated the effects of extracellularly delivered miRNA in the context of neuroinflammation. We identified several miRNAs specifically dysregulated in AD and/or neuroinflammatory states, which directly activate the single-stranded RNA sensors mouse TLR7 and human TLR7/8. Among them, extracellular miR-29a-5p induced cytokine and chemokine release from murine primary microglia, altered expression of TLR signalling elements, and enhanced Aβ phagocytosis. Furthermore, this miRNA induced neuronal injury dependent on microglial TLR7 expression, but also in a cell-autonomous fashion, in vitro. Intrathecal injection of miR-29a-5p into mice led to microglial accumulation and neuronal injury in the cerebral cortex through TLR7 after 3 days. Brains of wild-type and APP/PS1 mice, an established AD mouse model, treated with multiple intrathecal miR-29a-5p injections over 120 days exhibited changes in cytokine/chemokine expression and neuronal injury. RNAseq analysis of the cerebral cortex of both miRNA-treated genotypes revealed downregulation of MAPK-associated pathways.

Our study establishes AD-associated miRNAs such as miR-29a-5p as TLR7 agonists and signalling molecules for microglia, thereby altering the neuroinflammatory response.

The online version contains supplementary material available at 10.1186/s12974-025-03680-4.