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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

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Project description:Currently, more than 55 million people around the world suffer from dementia, and Alzheimer's disease-related dementia (ADRD) accounts for nearly 60-70% of all those cases. The spread of AD pathology and progressive neurodegeneration in the hippocampus and cerebral cortex is strongly correlated with cognitive decline in AD patients; however, the molecular underpinning of the ADRD causality is still unclear. Studies of postmortem AD brains and animal models of AD suggest that elevated endoplasmic reticulum (ER) stress may have a role in ADRD pathology through altered neurocellular homeostasis in brain regions associated with learning and memory. To study the ER stress-associated neurocellular response and its effects on neurocellular homeostasis and neurogenesis, we modeled an ER stress challenge using Thapsigargin (TG), a specific inhibitor of sarco/endoplasmic reticulum Ca2+ ATPase (SERCA), in induced pluripotent stem cell (iPSC)-derived neural stem cells (NSCs) of two individuals from our Mexican American Family Study (MAFS). High-content screening and transcriptomic analysis of the control and ER stress-challenged NSCs showed that NSC’s ER stress response resulted in a significant decline in NSC self-renewal and an increase in apoptosis and cellular oxidative stress. A total of 2300 genes were significantly (moderated t statistics FDR corrected p-value ≤ 0.05 and Fold Change absolute ≥ 2.0) differentially expressed (DE). Pathway enrichment and gene network analysis of DE genes suggests that all three unfolded protein response (UPR) pathways (PERK, IRE1, and ATF6) were significantly activated and cooperatively regulated the NSC’s transcriptional response to ER stress. Our results show that IRE1/XBP1 mediated transcriptional regulation of E2F1 and its downstream targets have a dominant role in inducing G1/S-phase cell cycle arrest in the ER stress-challenged NSCs. The ER stress-challenged NSCs also showed activation of CHOP-mediated apoptosis and dysregulation of synaptic plasticity and neurotransmitter homeostasis-associated genes. Overall, our results suggest that ER stress-associated attenuation of NSC self-renewal, increased apoptosis, and dysregulated synaptic plasticity and neurotransmitter homeostasis plausibly play a role in the causation of ADRD.

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

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