Alzheimers Dement. 2026 Oct;22(10):e71888. doi: 10.1002/alz.71888.

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.

PMID:42805933 | DOI:10.1002/alz.71888