Interleukin-4 induces neural stem cell plasticity by antagonizing Serotonin/HTR1 signaling that suppresses BDNF/NGFRA in adult zebrafish Alzheimer's disease model

ABSTRACT: In Alzheimer’s disease (AD), reduced neural stem cell (NSC) plasticity causes reduced neurogenesis. Therefore, supplying the brain with new neurons using endogenous neurogenic reservoir – NSCs - might counteract the progression of AD. However, the mechanisms that enhance NSC plasticity are unknown. We recently generated an AD model in adult zebrafish brain where NSCs could react by enhanced plasticity and neurogenesis, and identified Interleukin-4 (IL4) as a key factor underlying this ability. Although IL4 directly regulated NSCs through its receptor IL4R, it was not clear how IL4R-negative NSCs would enhance their proliferation. Here, by performing whole tissue and single cell transcriptomics, we report that IL4 regulates IL4R-negative NSCs through modulating tryptophan metabolism by reducing the availability of Serotonin (5-HT) that suppresses NSC plasticity. 5-HT receptor htr1+ is only expressed in periventricular neurons where 5-HT balances the expression of brain-derived neurotrophic factor (bdnf), which promotes NSC proliferation through its receptor NGFRA, which is predominantly expressed in IL4R-negative NSCs. AD conditions induce IL4 that reduce 5-HT levels, and suppresses the suppressive effect on BDNF levels. Elevated levels of BDNF activate, through NGFRA, the proliferative output of the IL4R-negative NSCs. 5-HT overexpression dramatically reduces BDNF and proliferative ability of NSCs. Our results identify a novel IL4-dependent balancing mechanism on NSC proliferation by 5-HT through an intermediary regulatory cascade via HTR1, and BDNF/NGFRA signaling between periventricular neurons and NSCs. Our findings mark the heterogeneity of NSCs in response to direct or indirect regulation by IL4 – a biomarker for neurodegeneration-induced NSC plasticity.

ORGANISM(S): Danio rerio

PROVIDER: GSE124162 | GEO | 2020/01/24

REPOSITORIES: GEO