The amyloid precursor protein (APP) intracellular domain (AICD) is a metabolic by-product of APP produced through sequential proteolytic cleavage by α-, β-, and γ-secretases. The interaction between AICD and Fe65 has been reported to impair adult neurogenesis in vivo. However, the exact role of AICD in mediating neural stem cell fate remains unclear. To identify the role of AICD in neuronal proliferation and differentiation, as well as to clarify the molecular mechanisms underlying the role of AICD in neurogenesis, we first generated a mouse model expressing the Rosa26-based AICD transgene. AICD overexpression did not alter the spatiotemporal expression pattern of full-length APP or accumulation of its metabolites. In addition, AICD decreased the newly generated neural progenitor cell (NPC) pool, inhibited the proliferation and differentiation efficiency of NPCs, and increased cell death both in vitro and in vivo. Given that abnormal neurogenesis is often associated with depression-like behavior in adult mice, we conducted a forced swim test and tail suspension test with AICD mice and found a depression-like behavioral phenotype in AICD transgenic mice. Moreover, AICD stimulated FOXO3a transcriptional activation, which in turn negatively regulated AICD. In addition, functional loss of FOXO3a in NPCs derived from the hippocampal dentate gyrus of adult AICD transgenic mice rescued neurogenesis defects. AICD also increased the mRNA expression of FOXO3a target genes related to neurogenesis and cell death. These results suggest that FOXO3a is the functional target of AICD in neurogenesis regulation. Our study reveals the role of AICD in mediating neural stem cell fate to maintain homeostasis during brain development via interaction with FOXO3a.

中文翻译：

---

FOXO3a 的 APP 细胞内结构域 (AICD) 依赖性调节抑制成人海马神经发生

淀粉样前体蛋白 (APP) 胞内结构域 (AICD) 是 APP 的代谢副产物，由 α-、β- 和 γ-分泌酶通过连续蛋白水解切割产生。据报道，AICD 和 Fe65 之间的相互作用会损害体内成体神经发生。然而，AICD 在介导神经干细胞命运中的确切作用仍不清楚。为了确定 AICD 在神经元增殖和分化中的作用，以及阐明 AICD 在神经发生中作用的分子机制，我们首先生成了一个表达基于 Rosa26 的 AICD 转基因的小鼠模型。AICD 过表达不会改变全长 APP 的时空表达模式或其代谢物的积累。此外，AICD 减少了新生成的神经祖细胞 (NPC) 池，抑制NPCs的增殖和分化效率，并增加体外和体内的细胞死亡。鉴于异常神经发生通常与成年小鼠的抑郁样行为有关，我们对 AICD 小鼠进行了强迫游泳测试和悬尾测试，并在 AICD 转基因小鼠中发现了抑郁样行为表型。此外，AICD 刺激了 FOXO3a 转录激活，进而负向调节 AICD。此外，来自成年 AICD 转基因小鼠海马齿状回的 NPC 中 FOXO3a 的功能丧失挽救了神经发生缺陷。AICD 还增加了与神经发生和细胞死亡相关的 FOXO3a 靶基因的 mRNA 表达。这些结果表明 FOXO3a 是 AICD 在神经发生调节中的功能靶点。