IL4/STAT6 Signaling Activates Neural Stem Cell Proliferation and Neurogenesis upon Amyloid-β42 Aggregation in Adult Zebrafish Brain
IL4/STAT6 Signaling Activates Neural Stem Cell Proliferation and Neurogenesis upon Amyloid-β42 Aggregation in Adult Zebrafish Brain
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DOI：
10.1016/j.celrep.2016.09.075
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发表时间：
2016-10-18
期刊：
影响因子：
8.8
通讯作者：
Kizil, Caghan
中科院分区：
文献类型：
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作者：
Bhattarai, Prabesh;Thomas, Alvin Kuriakose;Kizil, Caghan
由于内源性神经干/祖细胞（NSPCs）不能支持神经发生，人脑容易发生神经变性。为了研究可能介导再生生物体中神经变性诱导的NSPC可塑性的分子程序，我们通过侧脑室显微注射细胞穿透性A β 42衍生物在成年斑马鱼脑中产生了淀粉样蛋白β 42（A β 42）依赖性神经毒性模型。A β 42沉积在神经元中，并引起淀粉样蛋白病理生理学的表型：细胞凋亡、小胶质细胞活化、突触变性和学习缺陷。A β 42还诱导NSPC增殖和增强的神经发生。白细胞介素-4（IL 4）主要在神经元和小胶质细胞/巨噬细胞中响应于A β 42而被激活，并且足以通过NSPC中的IL 4受体经由STAT 6磷酸化来增加NSPC增殖和神经发生。我们的研究结果揭示了神经元和免疫细胞之间的串扰介导的IL 4/STAT 6信号，诱导斑马鱼大脑中的NSPC可塑性。
Human brains are prone to neurodegeneration, given that endogenous neural stem/progenitor cells (NSPCs) fail to support neurogenesis. To investigate the molecular programs potentially mediating neurodegeneration-induced NSPC plasticity in regenerating organisms, we generated an Amyloid-beta 42 (A beta 42)-dependent neurotoxic model in adult zebrafish brain through cerebroventricular microinjection of cell-penetrating A beta 42 derivatives. A beta 42 deposits in neurons and causes phenotypes reminiscent of amyloid pathophysiology: apoptosis, microglial activation, synaptic degeneration, and learning deficits. A beta 42 also induces NSPC proliferation and enhanced neurogenesis. Interleukin-4 (IL4) is activated primarily in neurons and microglia/macrophages in response to A beta 42 and is sufficient to increase NSPC proliferation and neurogenesis via STAT6 phosphorylation through the IL4 receptor in NSPCs. Our results reveal a crosstalk between neurons and immune cells mediated by IL4/STAT6 signaling, which induces NSPC plasticity in zebrafish brains.