# Microglia-Derived Extracellular Vesicles from Alzheimer’s Disease Patients Carry miRNAs Driving a Neuroinflammatory Response

## TL;DR

This study shows that microglia-derived extracellular vesicles from Alzheimer's patients contain miRNAs that trigger inflammation in the brain.

## Contribution

The novel finding is that AD patient-derived miRNAs in EVs activate TLR8 and induce a neuroinflammatory response.

## Key findings

- AD patient-derived EVs have distinct miRNA profiles compared to controls.
- Selected miRNAs activate human TLR8 and induce TNF release from microglia.
- These miRNAs may serve as potential biomarkers or therapeutic targets in AD.

## Abstract

Alzheimer’s disease (AD) represents the most common cause of dementia and urgently requires sensitive biomarkers and effective therapies. Extracellular vesicles represent membranous nano-sized particles secreted from cells, which serve as intercellular messengers participating in central nervous system (CNS) homeostasis, but also are implicated in AD pathogenesis. In addition, EVs containing disease-specific signatures, such as microRNAs (miRNAs), are considered as potent tools for the diagnosis and treatment of AD and other brain disorders. In this study, we used TMEM119 antibody to immunocapture microglia-derived EVs from cerebrospinal fluid (CSF) of AD patients and control subjects. EVs harvested from these CSF samples contained distinct disease-specific miRNA profiles, as assessed by small RNA sequencing. Using a HEK TLR reporter cell system, we found that these miRNA are potent activators of human TLR8, an established RNA sensor. Out of the miRNAs present in AD-associated EVs, selected oligonucleotides were synthesized and loaded into BV2 microglia-derived EVs. Exposure of primary murine microglia to these miRNA-loaded EVs led to TNF release from these cells, thereby driving a neuroinflammatory response. Taken together, putatively microglia-derived EVs from the CSF of AD patients contain miRNAs, which are capable of activating hTLR8 and inducing an inflammatory response from microglia.

The online version contains supplementary material available at 10.1007/s12035-026-05719-w.