Single cell analyses of the effects of Amyloid-beta42 and Interleukin-4 on neural stem/progenitor cell plasticity in adult zebrafish brain

AbstractNeural stem cells (NSCs) constitute the reservoir for new cells and might be harnessed for stem cell-based regenerative therapies. Zebrafish has remarkable ability to regenerate its brain by inducing NSC plasticity upon Alzheimer’s pathology. We recently identified that NSCs enhance their proliferation and neurogenic outcome in an Amyloid-beta42-based (Aβ42) experimental Alzheimer’s disease model in zebrafish brain and Interleukin-4 (IL4) is a critical molecule for inducing NSC proliferation in AD conditions. However, the mechanisms by which Aβ42 and IL4 affect NSCs remained unknown. Using single cell transcriptomics, we determined distinct subtypes of NSCs and neurons in adult zebrafish brain, identified differentially expressed genes after Aβ42 and IL4 treatments, analyzed the gene ontology and pathways that are affected by Aβ42 and IL4, and investigated how cell-cell communication is altered through secreted molecules and their receptors. Our results constitute the most extensive resource in the Alzheimer’s disease model of adult zebrafish brain, are likely to provide unique insights into how Aβ42/IL4 affects NSC plasticity and yield in novel drug targets for mobilizing neural stem cells for endogenous neuro-regeneration.

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Neuron-glia interaction through Serotonin-BDNF-NGFR axis enables regenerative neurogenesis in Alzheimer’s model of adult zebrafish brain

10.1101/748970 ◽

2019 ◽

Author(s):

Prabesh Bhattarai ◽

Mehmet Ilyas Cosacak ◽

Violeta Mashkaryan ◽

Sevgican Yilmaz ◽

Stanislava Dimitrova Popova ◽

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Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Experimental Models ◽

Interleukin 4 ◽

List Type ◽

Adult Zebrafish ◽

Bdnf Expression ◽

Zebrafish Brain ◽

Amyloid Toxicity ◽

The Brain

AbstractIt was recently suggested that supplying the brain with new neurons could counteract Alzheimer’s disease. This provocative idea requires further testing in experimental models where the molecular basis of disease-induced neuronal regeneration could be investigated. We previously found that zebrafish stimulates neural stem cell (NSC) plasticity and neurogenesis in Alzheimer’s disease and could help to understand the mechanisms to be harnessed for develop new neurons in diseased mammalian brains. Here, by performing single-cell transcriptomics, we found that Amyloid toxicity-induced Interleukin-4 induces NSC proliferation and neurogenesis by suppressing the tryptophan metabolism and reducing the production of Serotonin. NSC proliferation was suppressed by Serotonin via downregulation of BDNF-expression in Serotonin-responsive periventricular neurons. BDNF enhances NSC plasticity and neurogenesis via NGFRA/NFkB signaling in zebrafish but not in rodents. Collectively, our results suggest a complex neuron-glia interaction that regulates regenerative neurogenesis after Alzheimer’s disease conditions in zebrafish.Key findings-Amyloid-induced Interleukin-4 suppresses Serotonin (5-HT) production in adult zebrafish brain-5-HT affects htr1-expresing neurons and suppresses bdnf expression-BDNF enhances plasticity in neural stem cells via NGFRA/NFkB signaling-BDNF/NGFRA signaling is a neuro-regenerative mechanism in zebrafish but not in mammals.

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