GLP-1R agonist semaglutide protects human forebrain organoids from cholesterol-induced neurotoxicity
- Design
- Cell / in-vitro
- Drugs
- Semaglutide
- Assessment
- Not yet reviewed by a person · added Oct 4, 2026
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Abstract
[INTRODUCTION] Dysregulated cholesterol metabolism represents a critical metabolic stressor in the central nervous system, contributing to neuronal injury across multiple neurological conditions, including Alzheimer's disease (AD). While glucagon-like peptide-1 receptor (GLP-1R) agonists show neuroprotective potential, their capacity to directly mitigate cholesterol-induced metabolic stress in human neural cells remains to be established. [METHODS] Here, we modeled metabolic stress using human induced pluripotent stem cell-derived forebrain organoids exposed to cholesterol overload. The protective effects of the GLP-1R agonist semaglutide were characterized by integrating bulk/single-cell transcriptomics, calcium imaging, and biochemical assays. Furthermore, clinical translatability was supported by mapping organoid expression signatures against human post mortem neurodegenerative brain datasets. [RESULTS] Cholesterol overload induced cellular stress and transcriptomic alterations that partially overlapped with AD-associated signatures. Semaglutide protected neural cells from lipotoxic injury. Intracellularly, GLP-1R activation engaged the cyclic adenosine 3',5'-monophosphate-protein kinase A and phosphoinositide 3 kinase-protein kinase B-mechanistic target of rapamycin signaling pathways, consistent with reduced lipid droplet accumulation and oxidative stress. Intercellularly, single-cell analysis indicated partial preservation of disrupted cellular communication, including the neurotrophic midkine signaling network. Functionally, semaglutide stabilized cellular calcium activity patterns under metabolic stress. [DISCUSSION] These findings highlight the role of cholesterol homeostasis in maintaining neuronal integrity and position GLP-1R signaling as a candidate protective axis under metabolic stress, offering insights into therapeutic strategies for AD and broader neurodegenerative disorders.