3D Culture Method for Alzheimer's Disease Modeling Reveals Interleukin-4 Rescues Aβ42-Induced Loss of Human Neural Stem Cell Plasticity

Publication date: 2 July 2018
Source:Developmental Cell, Volume 46, Issue 1
Author(s): Christos Papadimitriou, Hilal Celikkaya, Mehmet I. Cosacak, Violeta Mashkaryan, Laura Bray, Prabesh Bhattarai, Kerstin Brandt, Heike Hollak, Xin Chen, Shuijin He, Christopher L. Antos, Weilin Lin, Alvin Kuriakose Thomas, Andreas Dahl, Thomas Kurth, Jens Friedrichs, Yixin Zhang, Uwe Freudenberg, Carsten Werner, Caghan Kizil
Neural stem cells (NSCs) constitute an endogenous reservoir for neurons that could potentially be harnessed for regenerative therapies in disease contexts such as neurodegeneration. However, in Alzheimer's disease (AD), NSCs lose plasticity and thus possible regenerative capacity. We investigate how NSCs lose their plasticity in AD by using starPEG-heparin-based hydrogels to establish a reductionist 3D cell-instructive neuro-microenvironment that promotes the proliferative and neurogenic ability of primary and induced human NSCs. We find that administration of AD-associated Amyloid-β42 causes classical neuropathology and hampers NSC plasticity by inducing kynurenic acid (KYNA) production. Interleukin-4 restores NSC proliferative and neurogenic ability by suppressing the KYNA-producing enzyme Kynurenine aminotransferase (KAT2), which is upregulated in APP/PS1dE9 mouse model of AD and in postmortem human AD brains. Thus, our culture system enables a reductionist investigation of regulation of human NSC plasticity for the identification of potential therapeutic targets for intervention in AD.

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Teaser

Papadimitriou et al. developed a starPEG-heparin-based hydrogel 3D neuro-microenvironment that promotes human neural stem cell proliferative and neurogenic capacity. Using the system to model Alzheimer's disease (AD) uncovered kynurenic acid/IL-4 interplay, which is also observed in AD mouse and human brains, suggesting its utility for reductionist investigation of AD therapeutic targets.


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