Fluoxetine Repurposing Mitigates Alzheimer’s Disease Pathology via the GSK3β–CREB–ADAM10 Axis

TL;DR

Fluoxetine, an antidepressant, may help reduce Alzheimer's disease symptoms by targeting specific brain pathways in mice.

Contribution

Fluoxetine's novel therapeutic potential in Alzheimer's via the GSK3β–CREB–ADAM10 pathway is demonstrated in a mouse model.

Findings

Fluoxetine reduced amyloid plaques and inflammation in the brains of 5xFAD mice.

Fluoxetine increased GSK3β phosphorylation, CREB activation, and ADAM10 expression in mice and neuronal cells.

GSK3β inhibition, not CaMKII inhibition, modulated CREB and ADAM10 in SH-SY5Y cells.

Abstract

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder in the aging population. Drug repurposing provides a cost-effective strategy to identify novel therapeutics that may mitigate age-associated pathologies. Here, we report the therapeutic potential of fluoxetine, a selective serotonin reuptake inhibitor commonly used as an antidepressant, in alleviating cognitive impairment and AD-like pathology in 5xFAD mice, a transgenic model of familial AD. Chronic fluoxetine administration significantly ameliorated anxiety-like behavior and cognitive deficits in 5xFAD mice, as assessed by open field, Y-maze, and novel object recognition tests. Fluoxetine treatment was associated with reduced amyloid plaque deposition in the hippocampus and cortex, attenuation of microglial activation, and decreased expression of inflammatory cytokines. At the molecular level, fluoxetine increased phosphorylation of GSK3β at Ser9, which was associated with enhanced CREB phosphorylation and upregulation of the α-secretase ADAM10. These effects were further examined in SH-SY5Y neuronal cells, where CREB phosphorylation and ADAM10 expression were significantly modulated by GSK3β inhibition, whereas CaMKII inhibition had no detectable effect under our experimental conditions. Our findings suggest that fluoxetine modulates amyloid-associated signaling pathways in the 5xFAD model, in part through regulation of the GSK3β-CREB signaling framework. These results provide mechanistic insight into how fluoxetine may influence APP processing in an amyloid-driven pathological context, although further studies are required to clarify its translational implications in human AD.

Figures