# Exploration of Cytokines That Impact the Therapeutic Efficacy of Mesenchymal Stem Cells in Alzheimer’s Disease

## TL;DR

This study explores how specific cytokines from mesenchymal stem cells affect Alzheimer's disease treatment outcomes.

## Contribution

The study identifies distinct roles of HGF, TNFR1, and BDNF cytokines in reducing Alzheimer's pathology and neuroinflammation.

## Key findings

- Silencing HGF mainly reduced Aβ/Tau clearance, while silencing TNFR1 or BDNF had modest effects on this.
- TNFR1 and BDNF silencing more strongly weakened anti-neuroinflammation effects of MSCs.
- All three cytokines partially contributed to oxidative stress reduction and cognitive improvements.

## Abstract

Current therapies for Alzheimer’s disease (AD) includes acetylcholinesterase inhibitors, NMDA receptor antagonists, and amyloid beta (Aβ)/Tau-targeting drugs. While these drugs improve cognitive decline and target the pathological mechanisms, their outcomes still are still in debate. Mesenchymal stem cells (MSCs) offer a regenerative approach by modulating neuroinflammation and promoting neuroprotection. Although the paracrine of MSCs is efficient in various AD preclinical studies and the exosomes of MSCs have entered clinical trials, the key cytokines driving the efficacy remain unclear. Here, we evaluated human umbilical cord-derived MSCs (hUC-MSCs) and employed gene-silenced MSCs (siHGF-MSCs, siTNFR1-MSCs, siBDNF-MSCs) in APP/PS1 AD mice to investigate specific mechanisms. hUC-MSCs significantly reduced Aβ/Tau pathology and neuroinflammation, with cytokine-specific contributions: silencing HGF predominantly reduced Aβ/Tau clearance, although silencing TNFR1 or BDNF showed modest effects; silencing TNFR1 or BDNF more prominently weakened anti-neuroinflammation, while silencing HGF exerted a weaker influence. All three cytokines partially contributed to oxidative stress reduction and cognitive improvements. Our study highlights MSC-driven AD alleviation as a multifactorial strategy and reveals specific cytokines alleviating different aspects of AD pathology.