Arhgef7 as a key target for enriched environment rescuing spatial cognitive deficits and anxiety-like behaviors in a mouse model of Alzheimer's disease following early social isolation.

Background: Both social and physical environmental factors influence the progression of Alzheimer's disease (AD), but the underlying mechanisms are not yet fully understood. This study aims to investigate how an enriched environment (EE) alleviates the detrimental effects of early social isolation (SI) on AD-like pathophysiology.

Methods: Four-week-old 5×FAD transgenic mice were randomly divided into group-housed and isolated groups. After 3 weeks, the mice were further raised in either a physical EE or a standard environment for an additional 3 weeks. Subsequently, these experimental subjects underwent a two-week of behavioral tests while maintaining their original housing conditions unchanged, followed by neuropathological analyses. A series of experiments were conducted on the medial prefrontal cortex (mPFC), including transcriptome sequencing, cellular localization, and knockdown and overexpression of a candidate gene, to identify the key molecules through which physical EE alleviates SI-induced AD-like alterations. The protective effects of the identified gene on cultured forebrain neurons exposed to β-amyloid stimulation, as well as its associated signaling pathways, were also investigated.

Results: EE enhanced cognitive function and alleviated anxiety-like behavior in SI-5×FAD mice, partially reversing dendritic and synaptic loss and glial cell activation in the mPFC. However, it did not mitigate deficits in social and cooperative behaviors, hypomyelination, or β-amyloid deposition. Notably, group-housed 5×FAD mice raised in the EE exhibited alleviation of the aforementioned AD-like phenotypes. Transcriptomic and bioinformatic analyses pinpointed Rho guanine nucleotide exchange factor 7 (Arhgef7) as a pivotal mediator of the beneficial effects of physical EE. Arhgef7 overexpression in mPFC neurons enhanced dendritic and synaptic growth and alleviated spatial cognitive impairments and anxiety-like behavior in SI-5×FAD mice, but it did not correct hypomyelination or social behavior deficits. Consistently, knockdown of Arhgef7 in mPFC neurons of group-housed 5×FAD mice selectively impaired neuronal processes and spatial cognition, and increased anxiety-like behavior. Mechanistically, Arhgef7 protected cortical neurons from β-amyloid toxicity by activating the Wnt signaling pathway.

Conclusion: Arhgef7 in mPFC neurons is essential for the physical components of EE selectively alleviating spatial cognitive deficits and anxiety-like behaviors in early isolated AD model mice, serving as a potential target for the prevention and treatment of AD.