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

Abstract

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.

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

“…Since Aβ42/IL4 enhances neural stem cell (NSC) proliferation in adult zebrafish brain (Bhattarai et al, 2017a;Bhattarai et al, 2016;Bhattarai et al, 2017b;Kizil, 2018;Kizil and Bhattarai, 2018b) and they downregulate 5-HT ( Figure 1E,F), we hypothesized that 5-HT could be negatively affecting NSC plasticity. To test this, we injected 5-HT into adult zebrafish brain and analyzed the proliferation of NSCs (S100b/PCNA double positive cells) (Figure 2A-C).…”

“…Amyloid-β42 (Aβ42) synthesis was performed as described . Cerebroventricular microinjection in adult zebrafish brain were performed as previously described (Bhattarai et al, 2017a;Bhattarai et al, 2016;Bhattarai et al, 2017b). PBS (1μl), Aβ42 (1 μl, 20 μM), IL4 (1 μl, 10 μg/ml), BDNF (1 μl, 100ng/ml), 5-HT (1 μl, 100 μM), ngfra morpholino (1μl, 10uM) were injected.…”

“…Therefore, examining how NSCs could be made proliferative and neurogenic during the course of AD could provide important clinical ramifications towards the treatment of this disease (Kizil and Bhattarai, 2018a); however, little is known about the mechanisms by which neural stem cells would enhance their proliferative response (Dong et al, 2019;Kempermann et al, 2018;Morrens et al, 2012). Recently, we established a zebrafish model, which can recapitulate the symptoms of AD in humans such as neuronal death, synaptic degeneration, chronic inflammation and cognitive decline (Bhattarai et al, 2017a;Bhattarai et al, 2016). Interestingly, in contrast to humans, zebrafish brain could enhance NSC proliferation and neurogenesis through a previously unidentified neuro-immune regulation involving Interleukin-4 (IL4).…”

Neuronal IL‐4Rα modulates neuronal apoptosis and cell viability during the acute phases of cerebral ischemia

“…This cytokine receptor complex is associated with diverse immune and inflammatory responses , but recent studies have suggested critical roles for this cytokine receptor complex in the brain. Diminished IL‐4 levels in the aging brain may lead to cognitive decline and increased risk of Alzheimer's disease , and in zebrafish brain displaying an Alzheimer's disease‐like phenotype, activation of IL‐4 coupled with its receptor IL‐4Rα promotes neural stem cell proliferation and neurogenesis . Furthermore, several clinical and animal studies have demonstrated that IL‐4 can function as a protective modulator, improving tissue recovery after ischemic stroke onset.…”

Interleukin 4 (IL-4) in Urinary Schistosomiasis as a Diagnostic Biomarker During Its Reinfection- A Review

“…Upon activation by IL-4, Th2 cells subsequently produce additional IL-4 in a positive feedback loop [11] and has recently be found to initiate a regeneration cascade through phosphorylation of its intracellular effector STAT6 in an experimental Alzheimer's disease model in adult zebra fish brain [12]. When granulomatous reaction occur following infection by S. heamatobium, the Antigen Presenting Cells (APC) process the exogenous antigen of the adult worm into antigen peptides and present it on the receptor referred to as Major Histocompactability Complex (MHC II) of Helper T cells.…”