Interleukin-4 restores neurogenic plasticity of the primary human neural stem cells through suppression of Kynurenic acid production upon Amyloid-beta42 toxicity

Abstract

The immune response is an important determinant of the plasticity and neurogenic capacity of neural stem cells (NSCs) upon amyloid-beta42 (Aβ42) toxicity in Alzheimer’s disease (AD). However, the direct effects of individual immuno-modulatory effectors on NSC plasticity remain to be elucidated and are the motivation for reductionist tissue-mimetic culture experiments. Using starPEG-Heparin hydrogel system that provides a defined 3D cell-instructive neuro-microenvironment culture system, sustains high levels of proliferative and neurogenic activity of human NSCs, and recapitulates the fundamental pathological consequences of Amyloid toxicity upon Aβ42 administration, we found that the anti-inflammatory cytokine interleukin-4 (IL4) restores the plasticity and neurogenic capacity of NSCs by suppressing the Aβ42-induced kynurenic acid-producing enzyme kynurenine aminotransferase 2 (KAT2), which we also found to be upregulated in the brains of the AD model, APP/PS1dE9 mouse. Our transcriptome analyses showed that IL4 treatment restores the expression levels of NSC and cortical subtype markers. Thus, our dissective neuro-microenvironment culture revealed IL4-mediated neuroinflammatory crosstalk for human NSC plasticity and predicted a new mechanistic target for therapeutic intervention in AD.

GATA3 Promotes the Neural Progenitor State but Not Neurogenesis in 3D Traumatic Injury Model of Primary Human Cortical Astrocytes

“…Recently, we have developed a 3D culture system based on starPEG-Heparin hydrogel system using pHAs and found that 3D topology of the cultures dictate a better resemblance of the human neural stem cells and neurons to their in vivo counterparts (Papadimitriou et al, 2017a,b, 2018). Given that 3D cultures promote an advanced and more tissue-mimetic physiology of the human brain cells (Murphy et al, 2017), we decided to perform our experiments in our starPEG-Heparin 3D cultures to address whether 3D system would provide better conditions compared to 2D and whether GATA3 has a different effect.…”