Wang Yimiao, Wang Ze, Li Yue, Cao Min, Zhang Shuying, Ding Shixin, Chen Sijia, Jin Yuxi, Zhang Yanli, Gao Junying, Xiao Ming
Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China.
Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, 214000, China.
Alzheimers Res Ther. 2025 Jul 1;17(1):143. doi: 10.1186/s13195-025-01797-5.
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.
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.
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.
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.
社会和物理环境因素均会影响阿尔茨海默病（AD）的进展，但其潜在机制尚未完全明确。本研究旨在探究丰富环境（EE）如何减轻早期社会隔离（SI）对AD样病理生理的有害影响。
将4周龄的5×FAD转基因小鼠随机分为群居组和隔离组。3周后，将小鼠进一步置于物理EE或标准环境中饲养3周。随后，这些实验对象在保持原饲养条件不变的情况下进行为期两周的行为测试，之后进行神经病理学分析。在内侧前额叶皮质（mPFC）上进行了一系列实验，包括转录组测序、细胞定位以及候选基因的敲低和过表达，以确定物理EE减轻SI诱导的AD样改变所通过的关键分子。还研究了所鉴定基因对暴露于β-淀粉样蛋白刺激的培养前脑神经元的保护作用及其相关信号通路。
EE增强了SI-5×FAD小鼠的认知功能并减轻了焦虑样行为，部分逆转了mPFC中的树突和突触损失以及胶质细胞活化。然而，它并未减轻社交和合作行为缺陷、髓鞘形成不足或β-淀粉样蛋白沉积。值得注意的是，在EE中饲养的群居5×FAD小鼠表现出上述AD样表型的减轻。转录组学和生物信息学分析确定Rho鸟嘌呤核苷酸交换因子7（Arhgef7）是物理EE有益作用的关键介导因子。mPFC神经元中Arhgef7的过表达增强了树突和突触生长，并减轻了SI-5×FAD小鼠的空间认知障碍和焦虑样行为，但并未纠正髓鞘形成不足或社交行为缺陷。同样，群居5×FAD小鼠mPFC神经元中Arhgef7的敲低选择性地损害了神经元突起和空间认知，并增加了焦虑样行为。从机制上讲，Arhgef7通过激活Wnt信号通路保护皮质神经元免受β-淀粉样蛋白毒性的影响。
mPFC神经元中的Arhgef7对于EE的物理成分选择性减轻早期隔离AD模型小鼠的空间认知缺陷和焦虑样行为至关重要，可作为AD预防和治疗的潜在靶点。
