1. Academic Validation
  2. Amyloid precursor protein intracellular domain-dependent regulation of FOXO3a inhibits adult hippocampal neurogenesis

Amyloid precursor protein intracellular domain-dependent regulation of FOXO3a inhibits adult hippocampal neurogenesis

  • Neurobiol Aging. 2020 Nov;95:250-263. doi: 10.1016/j.neurobiolaging.2020.07.031.
Mei Jiang 1 Sarivin Vanan 2 Hai-Tao Tu 2 Wei Zhang 2 Zhi-Wei Zhang 2 Sook-Yoong Chia 2 Se Eun Jang 2 Xiao-Xia Zeng 2 Wei-Ping Yu 3 Jie Xu 4 Kai-Hua Guo 5 Li Zeng 6
Affiliations

Affiliations

  • 1 Department of Neurobiology and Anatomy, Sun Yat-Sen University Zhongshan School of Medicine, Guangzhou, PR China; Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute, Singapore.
  • 2 Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute, Singapore.
  • 3 Animal Gene Editing Laboratory, Biological resource Centre, A∗STAR, Singapore; Institute of Molecular and Cell Biology, A∗STAR, Proteos, Singapore.
  • 4 Department of Neurobiology and Anatomy, Sun Yat-Sen University Zhongshan School of Medicine, Guangzhou, PR China. Electronic address: xujie@mail.sysu.edu.cn.
  • 5 Department of Neurobiology and Anatomy, Sun Yat-Sen University Zhongshan School of Medicine, Guangzhou, PR China. Electronic address: guokh@mail.sysu.edu.cn.
  • 6 Neural Stem Cell Research Lab, Research Department, National Neuroscience Institute, Singapore; Neuroscience and Behavioral Disorders Program, DUKE-NUS Graduate Medical School, Singapore; Lee Kong Chian School of Medicine, Nanyang Technology University, Novena Campus, Singapore. Electronic address: Li_Zeng@nni.com.sg.
Abstract

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.

Keywords

AICD; Differentiation; FOXO3a; Neural progenitor cells; Neurogenesis; Proliferation.

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