Neuronal GSK3β Protects Against Amyloid Pathology by Regulating APP Degradation

Glycogen synthase kinase 3β (GSK3β) exhibits dysregulated activity in Alzheimer's disease (AD), yet its cell type-specific roles in driving disease pathogenesis remain poorly understood. To explore the neuronal role of GSK3β in β-amyloid (Aβ) pathogenesis, we conditionally deleted Gsk3β in 5 × FAD mice using CaMKIIα-Cre-mediated recombination. Neuronal Gsk3β deletion exacerbated AD pathology, including increased Aβ deposition, pronounced gliosis, and enhanced neuroinflammatory responses. Loss of GSK3β impaired amyloid precursor protein (APP) degradation, leading to its accumulation and subsequent Aβ overproduction. These findings identify neuronal GSK3β as a critical modulator of APP turnover and Aβ pathology, revealing a protective role against AD progression. These findings suggest that broad inhibition of GSK3β may not be an optimal therapeutic strategy for AD, highlighting the importance of cell type-specific targeting. Graphical Schematic illustrating the regulation of APP degradation by neuronal GSK3β in 5 × FAD mice. In the 5 × FAD model, GSK3β promotes APP degradation. Conditional knockout of Gsk3β impairs this process, resulting in APP accumulation. This leads to increased Aβ plaque formation and enhanced neuroinflammatory responses.