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Amyloid precursor protein intracellular domain-dependent regulation of FOXO3a inhibits adult hippocampal neurogenesis
- Source :
- Neurobiology of aging. 95
- Publication Year :
- 2020
-
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.
- Subjects :
- 0301 basic medicine
Genetically modified mouse
Male
Aging
Programmed cell death
Transgene
Neurogenesis
Mice, Transgenic
Biology
Hippocampus
03 medical and health sciences
Amyloid beta-Protein Precursor
0302 clinical medicine
Amyloid precursor protein
Animals
RNA, Messenger
Progenitor cell
Cell Proliferation
Neurons
General Neuroscience
Dentate gyrus
Forkhead Box Protein O3
Gene Expression Regulation, Developmental
Cell Differentiation
Neural stem cell
Cell biology
030104 developmental biology
biology.protein
Neurology (clinical)
Geriatrics and Gerontology
030217 neurology & neurosurgery
Developmental Biology
Subjects
Details
- ISSN :
- 15581497
- Volume :
- 95
- Database :
- OpenAIRE
- Journal :
- Neurobiology of aging
- Accession number :
- edsair.doi.dedup.....e163a2b1bc5b68096be7892376174a4c