FOXG1 Improves Cognitive Function in Alzheimer's Disease by Promoting Endogenous Neurogenesis

ABSTRACT Strategies aimed at enhancing the capacity of neural stem cells (NSCs) to generate multipotential, proliferative, and migratory cell populations capable of efficient neuronal differentiation are crucial for structural repair following neurodegenerative damage. The role of Forkhead‐box gene 1 (FOXG1) in pattern formation, cell proliferation, and specification has been established. However, its involvement in Alzheimer's disease (AD) remains largely unknown. Here, we investigated the association between Foxg1 gene variants and AD‐like behavioral deficits, amyloid‐β (Aβ) aggregate formation, as well as p21 expression. Furthermore, we explored whether targeting the FOXG1‐regulated cell cycle contributes to the promotion of adult neurogenesis in the context of AD. In this study, we successfully induced overexpression of FOXG1 in the hippocampus of AD brains through adeno‐associated virus‐ Foxg1 infusion. Activation of FOXG1 rescued spatial learning disabilities, short‐term memory deficits, and sensorimotor gating impairments observed in AD transgenic animals. By inhibiting p21 WAF1/cyclin‐dependent kinase interacting protein 1 ( p21 cip1/waf1 )‐mediated cell cycle arrest, FOXG1 facilitates the activation and proliferation of NSCs. Additionally, the Foxg1 gene promotes an increase in precursor population size and enhances neuroblast differentiation. These combined effects on proliferation and differentiation lead to the generation of postmitotic neurons within the hippocampus in AD animals. Together, these findings demonstrate the importance of cooperation between FOXG1 and p21 for maintaining NSC self‐renewal while facilitating neuronal lineage progression and contributing to endogenous neurogenesis during AD. Elevating levels of FOXG1 either pharmacologically or through alternative means could potentially serve as a therapeutic strategy for treating AD.