Interleukin-4 restores neurogenic plasticity of the primary human neural stem cells through suppression of Kynurenic acid production upon Amyloid-β42 toxicity

Papadimitriou, C.; Celikkaya, H.; Cosacak, M. I. I.; Mashkaryan, V.; Bhattarai, P.; Lin, W.; Thomas, A.; Zhang, Y.; Freudenberg, U.; Werner, C.; Kizil, C.

doi:10.1101/227306

bioRxiv · 10.1101/227306

Interleukin-4 restores neurogenic plasticity of the primary human neural stem cells through suppression of Kynurenic acid production upon Amyloid-β42 toxicity

Papadimitriou, C.·Celikkaya, H.·Cosacak, M. I. I.·Mashkaryan, V.·Bhattarai, P.·Lin, W.·Thomas, A.·Zhang, Y.·Freudenberg, U.·Werner, C.·Kizil, C.

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Abstract

The immune response is an important determinant of the plasticity and neurogenic capacity of neural stem cells (NSCs) upon amyloid-beta42 (A{beta}42) toxicity in Alzheimers 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 A{beta}42 administration, we found that the anti-inflammatory cytokine interleukin-4 (IL4) restores the plasticity and neurogenic capacity of NSCs by suppressing the A{beta}42-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.

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Papadimitriou, C., Celikkaya, H., Cosacak, M. I. I., Mashkaryan, V., Bhattarai, P., Lin, W., Thomas, A., Zhang, Y., Freudenberg, U., Werner, C., Kizil, C.. 2017-12-03. Interleukin-4 restores neurogenic plasticity of the primary human neural stem cells through suppression of Kynurenic acid production upon Amyloid-β42 toxicity. https://doi.org/10.1101/227306

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