阿尔茨海默病AD患者的海马神经环路发生损害，出现学习记忆障碍。AD有两个重要的病理特征和致病因素：Aβ多肽聚集形成淀粉样斑和tau蛋白过度磷酸化形成纤维缠结。我们在小鼠基因组中鉴定出新基因家族Rps23rg，是由小鼠Rps23 mRNA发生返座而起源。小鼠RPS23RG家族成员能够同时抑制Aβ产生和tau磷酸化。前期工作发现人RPS23 mRNA也发生返座，在人基因组中产生1个功能表达的同源蛋白hRPS23RG1。hRPS23RG1抑制Aβ产生和tau磷酸化，其表达在AD中明显降低。此外，下调小鼠Rps23rg会损害神经突触功能。我们将在诱导分化形成的人神经细胞中研究hRPS23RG1的生化特性、表达调控、对神经细胞分化和功能的影响、以及参与AD的机制。我们将应用病毒感染和构建基因敲除小鼠，调控海马区的RPS23RG水平，研究其在海马神经环路的功能以及对AD病理和学习记忆障碍的治疗作用。

Brain hippocampus is an important structural basis for learning and memory. Neural circuits of the hippocampus are impaired in Alzheimer’s disease (AD) patients, who have learning and memory defects. AD has two important pathological features: senile plaques composed of β-amyloid (Aβ) peptides and neurofibrillary tangles formed by hyperphosphorylated microtubule-binding protein tau. Excessive production and accumulation of Aβ in the brain is primary cause of AD. We previously identified a new mouse gene family, Rps23rg, originated through retroposition of the mouse Rps23 (ribosomal protein S23) mRNA and showed that RPS23RG proteins simultaneously suppress Aβ generation and tau phosphorylation. In preliminary data, we found that retroposition of the human RPS23 mRNA also resulted in a functionally expressed Rps23rg human homolog, which we call hRPS23RG1. Notably, hRPS23RG1 also inhibited Aβ generation and tau phosphorylation and its expression was markedly decreased in AD brain. In addition, we found that downregulation of mouse Rps23rg impaired synaptic function. In this project, we will study the characteristics and transcriptional regulation of hRPS23RG1, determine the molecular mechanism underlying hRPS23RG1-inhibited Aβ generation and tau phosphorylation, and explore the involvement of hRPS23RG1 in neuronal cell differentiation and in synaptic function, using neurons differentiated from human embryonic stem cells. By applying viral injection and generating Rps23rg gene knockout mice, we will modulate the levels of RPS23RG in mouse brain hippocampus and study the effects of RPS23RG on the hippocampal neural circuit functions, as well as on AD-like phenotypes in AD mice. Our study will elucidate the participation of RPS23RG in AD and provide new targets for disease intervention.