Department of Neurosurgery, Chi-Mei Medical Center, 901 Chung Hwa Road, Yung Kang City, Tainan, Taiwan.
Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan.
Pharmacol Rep. 2024 Oct;76(5):1032-1043. doi: 10.1007/s43440-024-00623-3. Epub 2024 Jul 16.
Dendritic spine dysfunction is a key feature of Alzheimer's disease (AD) pathogenesis. Human T-cell lymphoma invasion and metastasis 2 (TIAM2) is expressed in two isoforms, the full length (TIAM2L) and a short transcript (TIAM2S). Compared to TIAM2L protein, which is undetectable, TIAM2S protein is abundant in human brain tissue, especially the hippocampus, and can promote neurite outgrowth in our previous findings. However, whether enhanced hippocampal TIAM2S expression can alleviate cognitive deficits in Alzheimer's disease model mice remains unclear.
We crossbred 3xTg-AD with TIAM2S mice to generate an AD mouse model that carries the human TIAM2S gene (3xTg-AD/TIAM2S mice). The Morris water maze and object location tests assessed hippocampus-dependent spatial memory. Lentiviral-driven shRNA or cDNA approaches were used to manipulate hippocampal TIAM2S expression. Golgi staining and Sholl analysis were utilized to measure neuronal dendrites and dendritic spines in the mouse hippocampi.
Compared to 3xTg-AD mice, 3xTg-AD/TIAM2S mice displayed improved cognitive functions. According to the hippocampus is one of the earliest affected brain regions by AD, we further injected TIAM2S shRNA or TIAM2S cDNA into mouse hippocampi to confirm whether manipulating hippocampal TIAM2S expression could affect AD-related cognitive functions. The results showed that the reduced hippocampal TIAM2S expression in 3xTg-AD/TIAM2S mice abolished the memory improvement effect, whereas increased hippocampal TIAM2S levels alleviated cognitive deficits in 3xTg-AD mice. Furthermore, we found that TIAM2S-mediated memory improvement was achieved by regulating dendritic plasticity.
These results will provide new insights into connecting TIAM2S with AD and support the notion that TIAM2S should be investigated as potential AD therapeutic targets.
树突棘功能障碍是阿尔茨海默病（AD）发病机制的一个关键特征。人类 T 细胞淋巴瘤侵袭和转移 2（TIAM2）有两种异构体表达，全长（TIAM2L）和短转录本（TIAM2S）。与在人脑组织中不可检测的 TIAM2L 蛋白相比，TIAM2S 蛋白在人脑组织，特别是海马体中丰富，并能促进我们之前研究中的神经突生长。然而，增强海马 TIAM2S 表达是否能缓解阿尔茨海默病模型小鼠的认知缺陷尚不清楚。
我们将 3xTg-AD 与 TIAM2S 小鼠杂交，生成携带人 TIAM2S 基因的 AD 小鼠模型（3xTg-AD/TIAM2S 小鼠）。Morris 水迷宫和物体位置测试评估海马体依赖的空间记忆。慢病毒驱动的 shRNA 或 cDNA 方法用于操纵海马 TIAM2S 表达。高尔基染色和 Sholl 分析用于测量小鼠海马神经元的树突和树突棘。
与 3xTg-AD 小鼠相比，3xTg-AD/TIAM2S 小鼠表现出认知功能改善。根据 AD 最早受影响的大脑区域之一是海马体，我们进一步将 TIAM2S shRNA 或 TIAM2S cDNA 注入小鼠海马体，以确认操纵海马 TIAM2S 表达是否会影响与 AD 相关的认知功能。结果表明，3xTg-AD/TIAM2S 小鼠海马 TIAM2S 表达减少消除了记忆改善效应，而增加海马 TIAM2S 水平缓解了 3xTg-AD 小鼠的认知缺陷。此外，我们发现 TIAM2S 介导的记忆改善是通过调节树突可塑性实现的。
这些结果将为 TIAM2S 与 AD 之间的联系提供新的见解，并支持将 TIAM2S 作为潜在的 AD 治疗靶点进行研究的观点。
