IL4/STAT6 Signaling Activates Neural Stem Cell Proliferation and Neurogenesis upon Amyloid-β42 Aggregation in Adult Zebrafish Brain

• Published in: Cell reports (Cambridge) Vol. 17; no. 4; pp. 941 - 948
• Main Authors: Bhattarai, Prabesh, Thomas, Alvin Kuriakose, Cosacak, Mehmet Ilyas, Papadimitriou, Christos, Mashkaryan, Violeta, Froc, Cynthia, Reinhardt, Susanne, Kurth, Thomas, Dahl, Andreas, Zhang, Yixin, Kizil, Caghan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.10.2016; Elsevier
• Subjects: Aging - pathology; Alzheimer’s disease; Amyloid beta-Peptides - metabolism; Amyloid-β42; Animals; Brain - metabolism; Brain - pathology; Cell Plasticity; Cell Proliferation; Cognitive Sciences; inflammation; Interleukin-4 - metabolism; interlukin-4; Life Sciences; Microglia; Nerve Degeneration - pathology; neural stem cell; Neural Stem Cells - cytology; neuro-immune crosstalk; Neurobiology; neurodegeneration; Neurogenesis; Neurons; Neurons and Cognition; Peptide Fragments - metabolism; Phenotype; Protein Aggregates; Psychology and behavior; regeneration; Signal Transduction; STAT6; STAT6 Transcription Factor - metabolism; zebrafish; Zebrafish - metabolism; neural stem cell; Alzheimer’s disease; regeneration; inflammation; neurodegeneration; interlukin-4; STAT6; zebrafish; neuro-immune crosstalk; Amyloid-β42
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.09.075

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-β42 (Aβ42)-dependent neurotoxic model in adult zebrafish brain through cerebroventricular microinjection of cell-penetrating Aβ42 derivatives. Aβ42 deposits in neurons and causes phenotypes reminiscent of amyloid pathophysiology: apoptosis, microglial activation, synaptic degeneration, and learning deficits. Aβ42 also induces NSPC proliferation and enhanced neurogenesis. Interleukin-4 (IL4) is activated primarily in neurons and microglia/macrophages in response to Aβ42 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. [Display omitted] •Amyloid-β42 (Aβ42) forms aggregates in neurons of adult zebrafish brain•Aβ42 causes apoptosis, inflammation, synaptic loss, and memory deficits in zebrafish•Aβ42 leads to interleukin-4 (IL4) upregulation in neurons and microglia•IL4/STAT6 signaling induces neural stem cell proliferation Bhattarai et al. shows that adult zebrafish brain displays Alzheimer’s disease-like phenotypes after Amyloid-β42 (Aβ42) aggregation. Aβ42 can also activate neural stem cell proliferation and neurogenesis. Interleukin-4, which induces STAT6 phosphorylation, is a key factor for mediating the neuro-immune crosstalk between diseased neurons, immune cells, and stem cells.