Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
J Gerontol A Biol Sci Med Sci. 2024 Nov 1;79(11). doi: 10.1093/gerona/glae191.
TIAM Rac1-associated GEF 2 short-form protein (TIAM2S) is abundant in specific brain tissues, especially in the hippocampus, a brain region critical for processing and consolidation of spatial memory. However, how TIAM2S plasticizes the microstructure and circuits of the hippocampus to shape spatial memory as a neuroplastic regulator during aging remains to be determined. In this study, transgenic mice overexpressing human TIAM2S protein (TIAM2S-TG mice) were included, and interdisciplinary approaches, such as spatial memory tests and multiparametric magnetic resonance imaging sequences, were conducted to determine the role and the mechanism of TIAM2S in age-related spatial memory deficits. Despite no changes in their neural and glial markers and neuropathological hallmark expression of the hippocampus, behavioral tests showed that the TIAM2S-TG mice, and not wild-type (WT) mice, developed spatial memory impairment at 18 months old. The T2-weighted and diffusion tensor image analyses were performed to further study the possible role of TIAM2S overexpression in altering the hippocampal structure or neuronal circlets of the mice, increasing their vulnerability to developing spatial memory deficits during aging. The results revealed that the 12-month-old TIAM2S-TG mice had hippocampal dysplasticity, with larger volume, increased fiber numbers, and changed mean fractional anisotropy compared to those in the age-matched WT mice. The fiber tractography analysis exhibited significantly attenuated structural connectivity between the hippocampus and medial prefrontal cortex in the TIAM2S-TG mice. In conclusion, overexpression of TIAM2S, a detrimental factor affecting hippocampus plasticity, causes attenuation of the connectivity within hippocampus-mPFC circuits, leading to age-related spatial memory impairment.
TIAM Rac1 相关鸟苷酸交换因子 2 短型蛋白（TIAM2S）在特定脑组织中含量丰富，特别是在海马体中，海马体是处理和巩固空间记忆的关键脑区。然而，TIAM2S 如何作为神经可塑性调节剂，在衰老过程中使海马体的微结构和回路发生可塑性变化，从而塑造空间记忆，仍有待确定。在这项研究中，纳入了过表达人 TIAM2S 蛋白的转基因小鼠（TIAM2S-TG 小鼠），并采用空间记忆测试和多参数磁共振成像序列等多种学科方法，以确定 TIAM2S 在与年龄相关的空间记忆缺陷中的作用和机制。尽管 TIAM2S-TG 小鼠的海马神经和神经胶质标志物以及神经病理学特征标志物没有变化，但行为测试表明，18 个月大时，TIAM2S-TG 小鼠而非野生型（WT）小鼠出现了空间记忆障碍。进行 T2 加权和弥散张量成像分析，以进一步研究 TIAM2S 过表达在改变小鼠海马结构或神经元环方面的可能作用，增加它们在衰老过程中发生空间记忆缺陷的易感性。结果表明，与年龄匹配的 WT 小鼠相比，12 个月大的 TIAM2S-TG 小鼠的海马体存在发育不良，体积增大，纤维数量增加，平均各向异性分数改变。纤维束追踪分析显示，TIAM2S-TG 小鼠的海马体与内侧前额叶皮质之间的结构连接明显减弱。总之，TIAM2S 的过表达是影响海马体可塑性的有害因素，导致海马体- mPFC 回路的连接性减弱，从而导致与年龄相关的空间记忆障碍。
