Estrogen G‐Protein Coupled Receptor Antagonist G15 Promotes Tau Clearance in 2D and 3D Tauopathy Models

Several studies have investigated the efficacy of estrogen in age-related diseases, showing promising results in several models of neurodegeneration, such as Alzheimer's disease. Animal and cellular models indicate that estrogen and related compounds can reduce the accumulation of amyloid plaques and tau protein, which are associated with Alzheimer's disease. Therefore, it is crucial to develop appropriate models to study the neuroprotective effects of estrogen, and three-dimensional (3D) models have recently emerged as a viable alternative to animal testing. This study aimed to investigate the potential of 3D tauopathy models for drug testing, focusing on estrogen-related signaling. The results demonstrate that a scaffold-free neurospheroid with inducible tau protein expression allows for the observation of tau protein distribution throughout the spheroid. Moreover, the study found that the G-protein-coupled estrogen receptor antagonist, G15, reduced tau protein concentration in both 2D and 3D models. Thus, this study highlights the importance of estrogen-related compounds in 3D cultures, which could facilitate investigations into the mechanisms of action and the neuroprotective role of estrogen in neurodegenerative diseases.