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 T 细胞淋巴瘤侵袭和转移 2 (TIAM2) 以两种亚型表达，即全长转录本 (TIAM2L) 和短转录本 (TIAM2S)。与无法检测到的TIAM2L蛋白相比，TIAM2S蛋白在人脑组织尤其是海马中含量丰富，并且在我们之前的研究中可以促进神经突生长。然而，增强海马TIAM2S表达是否可以缓解阿尔茨海默病模型小鼠的认知缺陷仍不清楚。我们将3xTg-AD与TIAM2S小鼠杂交，产生携带人类TIAM2S基因的AD小鼠模型（3xTg-AD/TIAM2S小鼠）。莫里斯水迷宫和物体定位测试评估了海马体依赖性空间记忆。慢病毒驱动的 shRNA 或 cDNA 方法用于操纵海马 TIAM2S 表达。利用高尔基染色和Sholl分析测量小鼠海马神经元树突和树突棘。与3xTg-AD小鼠相比，3xTg-AD/TIAM2S小鼠表现出改善的认知功能。鉴于海马是AD最早受影响的大脑区域之一，我们进一步将TIAM2S shRNA或TIAM2S cDNA注射到小鼠海马中，以确认操纵海马TIAM2S表达是否可以影响AD相关的认知功能。结果显示，3xTg-AD/TIAM2S 小鼠海马 TIAM2S 表达减少消除了记忆改善作用，而海马 TIAM2S 水平增加则缓解 3xTg-AD 小鼠认知缺陷。此外，我们发现 TIAM2S 介导的记忆改善是通过调节树突可塑性来实现的。这些结果将为将 TIAM2S 与 AD 连接提供新的见解，并支持 TIAM2S 应作为潜在 AD 治疗靶点进行研究的观点。© 2024。作者）获得波兰科学院药理学研究所的独家许可。

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.© 2024. The Author(s) under exclusive licence to Maj Institute of Pharmacology Polish Academy of Sciences.