Semaglutide attenuates Alzheimer's disease model progression by targeting microglial NLRP3 inflammasome-mediated neuroinflammation and ferroptosis

Oct 31, 2025Experimental neurology

Semaglutide may slow Alzheimer's progression by reducing inflammation and cell death in brain immune cells

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Abstract

Semaglutide treatment rescued cognitive function in APP/PS1 mice and reduced amyloid beta accumulation.

SEM suppressed amyloid beta aggregation and tau hyper-phosphorylation in the hippocampus of APP/PS1 mice.
Inhibition of microglial NLRP3 activation by SEM was observed in both APP/PS1 mice and LPS + ATP-stimulated microglia.
SEM promoted microglial M2 polarization, which is associated with reduced neuroinflammation.
Alleviation of ferroptosis was linked to the activation of specific cellular pathways by SEM.
Microglia-specific NLRP3 knockdown led to decreased amyloid beta deposition and improved M2 polarization.

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Microglial activation driven by NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome signaling exacerbates Alzheimer's disease (AD) pathology through enhanced neuroinflammation and amyloid beta (Aβ) accumulation. Semaglutide (SEM) has attracted growing attention for its potential therapeutic effects in AD, while its underlying mechanisms remain unclear. In this study, we investigated the neuroprotective effects of SEM in both APP/PS1 transgenic mice and LPS + ATP-stimulated BV2 microglia. Our results demonstrate that SEM treatment rescued APP/PS1 mice from cognitive impairment and suppressed Aβ aggregation and tau hyper-phosphorylation in the hippocampus of APP/PS1 mice. Furthermore, we found that SEM inhibited microglial NLRP3 activation, promoted microglial M2 polarization and alleviated ferroptosis via NLRP3/nuclear factor kappa B (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1)/ cystine/glutamate antiporter SLC7A11 (xCT)/glutathione peroxidase 4 (GPX4) pathways in APP/PS1 mice and LPS + ATP-stimulated BV2 microglia. These findings were further corroborated by microglia-specific NLRP3 knockdown, which reduced Aβ deposition, promotied M2 polarization, attenuated neuroinflammation, and suppressed ferroptosis. Our findings provide further theoretical support for the clinical application of SEM in AD treatment, while also establishing a scientific foundation for AD therapeutic strategies targeting the microglial NLRP3 pathway.

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Semaglutide attenuates Alzheimer's disease model progression by targeting microglial NLRP3 inflammasome-mediated neuroinflammation and ferroptosis

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