海马突触可塑性下降在阿尔茨海默病（AD）发病进程中占据重要地位，发掘增强突触可塑性的潜在靶点成为近年来研究及治疗AD的新方向。我们前期研究发现：半乳糖凝集素-3（Gal-3）在AD患者血清中上调，且与认知损伤相关；Gal-3损伤突触可塑性并伴随肌动蛋白异常组装和微管系统紊乱。据此，本项目提出假说：Gal-3结合EphA4受体过度激活RhoA/ROCK通路引起细胞骨架动态周转紊乱，进而损伤海马突触可塑性，最终促进AD中认知障碍。本研究拟采用3月龄和11月龄APP/PS1小鼠，将Gal-3的RNA或干扰RNA慢病毒微注射到海马分别过表达或敲减此脑区Gal-3，从正反两方面研究中枢Gal-3在AD突触可塑性损伤中的作用，并在神经元中经重组Gal-3及其抑制剂进一步确证，最后阐明Gal-3损伤突触可塑性的信号通路。本项目将为增强突触可塑性提供潜在靶点，并为靶向Gal-3的AD新药研究奠定科学基础。

Hippocampal synaptic plasticity decline plays an important role in the pathogenesis of Alzheimer's disease (AD). Exploring the new molecular target for enhancing synaptic plasticity is the new strategy on study and therapy of AD. Our previous studies have found that galectin-3 (Gal-3) level is increased in the serum of AD patients and significantly correlated with cognitive impairment. Gal-3 treatment induces synaptic plasticity impairment, accompanied by abnormal actin rearrangement and microtubule disorder. In view of the above, we hypothesize that central Gal-3 might induce synaptic plasticity decline and cognitive impairment by deregulating cytoskeleton dynamics through binding with EphA4 receptor and then over-activating RhoA/ROCK signaling. In this project, Gal-3 will be overexpressed or knocked down via micro-injecting the lentiviral vector encoding the RNA or shRNA for Gal-3 gene into the hippocampi of TgAPP/PS1 mice aged 3 or 11 months. The role of central Gal-3 in hippocampal synaptic plasticity decline will be investigated from two aspects of positive and negative regulation, and confirmed by Gal-3 and Gal-3 inhibitor in the primary cultured hippocampal neurons. At last, we will clarify the signaling of Gal-3-inducing synaptic plasticity impairment. The project will help to find the target for enhancing synaptic plasticity and subsequently lay the foundation for research and development of new anti-AD drug targeting Gal-3.