Type 1 Interleukin-4 Signaling Obliterates Mouse Astroglia in vivo but Not in vitro

Violeta Mashkaryan,Caghan Kizil,Andreas Petzold,Mehmet Ilyas Cosacak,Roger Lefort,Prabesh Bhattarai,Kerstin Brandt,Tohid Siddiqui,Stanislava Popova,Andreas Dahl,Nambirajan Govindarajan,Susanne Reinhardt

doi:10.3389/fcell.2020.00114

Abstract

Recent findings suggest that reduced neurogenesis could be one of the underlying reasons for the exacerbated neuropathology in humans, thus restoring the neural stem cell proliferation and neurogenesis could help to circumvent some pathological aspects of Alzheimer’s disease. We recently identified Interleukin-4/STAT6 signaling as a neuron–glia crosstalk mechanism that enables glial proliferation and neurogenesis in adult zebrafish brain and 3D cultures of human astroglia, which manifest neurogenic properties. In this study, by using single cell sequencing in the APP/PS1dE9 mouse model of AD, we found that IL4 receptor (Il4r) is not expressed in mouse astroglia and IL4 signaling is not active in these cells. We tested whether activating IL4/STAT6 signaling would enhance cell proliferation and neurogenesis in healthy and disease conditions. Lentivirus-mediated expression of IL4R or constitutively active STAT6VT impaired the survival capacity of mouse astroglia in vivo but not in vitro. These results suggest that the adult mouse brain generates a non-permissive environment that dictates a negative effect of IL4 signaling on astroglial survival and neurogenic properties in contrast to zebrafish brains and in vitro mammalian cell cultures. Our findings that IL4R signaling in dentate gyrus (DG) of adult mouse brain impinges on the survival of DG cells implicate an evolutionary mechanism that might underlie the loss of neuroregenerative ability of the brain, which might be utilized for basic and clinical aspects for neurodegenerative diseases.

Highlights

Alzheimer’s disease (AD) is a progressive and yet irreversible neurodegenerative disease
Modulation of inflammatory environment and efforts to retain the synaptic integrity during the course of AD are promising approaches to revert the neuropathological changes of the disease, yet other cellular paradigms such as neurogenesis could be involved in manifestation of AD phenotypes (Amor et al, 2010; Rodriguez and Verkhratsky, 2011; Heneka et al, 2013; Nisbet et al, 2015; De Strooper and Karran, 2016; Dzamba et al, 2016; Scheltens et al, 2016; Kizil, 2018)
We identified that in a zebrafish model of AD, Amyloidmediated pathology induces neural stem cell proliferation and subsequent neurogenesis and integration of newborn neurons into the brain despite the prevalent neurodegenerative toxicity (Bhattarai et al, 2016, 2017a,b, 2020; Cosacak et al, 2019)

Summary

Introduction

Alzheimer’s disease (AD) is a progressive and yet irreversible neurodegenerative disease. One of the early symptoms of AD in mouse models is reduced neural stem cell proliferation and neurogenesis (Haughey et al, 2002a,b; Ziabreva et al, 2006), and increased neurogenesis – when experimentally coupled to neuronal survival in AD mouse brains – can revert the cognitive decline (Choi et al, 2018). These findings suggest that enhancing neurogenesis might be a way to counteract AD progression by “regenerating” neurons. Our knowledge of the molecular mechanisms by which neural stem cells could enhance their proliferation and neurogenic ability in disease conditions is limited

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