FOXG1 as a Potential Therapeutic Target for Alzheimer's Disease with a Particular Focus on Cell Cycle Regulation

Background: Several recent findings have revealed that targeting of cell cycle reentry and (or) progression may provide an opportunity for the therapeutic intervention of Alzheimer's disease (AD). FOXG1 has been shown to play important roles in pattern formation, cell proliferation, and cell specification. Thus far, the roles of FoxG1 and its involvement in AD are largely unknown. Objective: Our study aimed to explore the intervention effect of FOXG1 on AD pathology and its potential mechanism with a particular focus on cell cycle regulation. Methods: We investigated the association of Foxg1 gene variants with AD-like behavioral deficits, p21 expression, neuronal apoptosis, and amyloid-beta (A beta) aggregate formation; we further determined whether targeting FOXG1-regulated cell cycle has therapeutic potential in AD. Results: Paralleling AD-like behavioral abnormalities, neuronal apoptosis, and A beta deposits, a significant reduction in the expression of FOXG1 was observed in APP/PS1 mice at 6 months of age. Using the APP/PS1;Foxg1(fl/fl)-CreAAV mouse line, we found that FOXG1 potentially antagonized cell cycle reentry by negatively regulating the levels of p21-activated kinase (PAK3). By reducing p21(cip1)-mediated arrest at the G(2) stage and regulating cyclin A1- and cyclin B-dependent progression patterns of the cell cycle, FOXG1 blocked neuronal apoptosis and A beta deposition. Conclusion: These results indicate that FOXG1 contributes to the regulation of the neuronal cell cycle, thereby affecting brain abnormalities in AD. An elevation of the FOXG1 level, either pharmacologically or through other means, could present a therapeutic strategy for AD.

Automated summary

This study explores the role of FOXG1 in Alzheimer's disease (AD) and its involvement in cell cycle regulation. By negatively regulating the levels of p21-activated kinase (PAK3), FOXG1 inhibits cell cycle reentry and reduces neuronal apoptosis and Aβ deposition. Increasing the level of FOXG1 may present a therapeutic strategy for AD.