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Dev Cell. 2018 Jul 2;46(1):85-101.e8. doi: 10.1016/j.devcel.2018.06.005.

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

Author information

1
German Center for Neurodegenerative Diseases (DZNE) Dresden, Helmholtz Association, Arnoldstr. 18, 01307 Dresden, Germany; Center for Regenerative Therapies (CRTD), Technische Universität Dresden, Fetscherstr. 105, 01307 Dresden, Germany.
2
Leibniz Institute of Polymer Research Dresden, Max Bergmann Center of Biomaterials Dresden, Hohe Str. 6, 01069 Dresden, Germany; Institute of Health Biomedical Innovation (IHBI), Queensland University of Technology, 60 Musk Avenue, Kelvin Grove 4059, Australia.
3
School of Life Sciences and Technology, ShanghaiTech University, Shanghai 201210, People's Republic of China.
4
School of Life Sciences and Technology, ShanghaiTech University, Shanghai 201210, People's Republic of China; Institut für Pharmakologie und Toxikologie, Technische Universität Dresden Medizinische Fakultät, Fetscherstr. 74, 01307 Dresden, Germany.
5
B CUBE, Center for Molecular Bioengineering, TU Dresden, Arnoldstr. 18, 10307 Dresden, Germany.
6
Center for Regenerative Therapies (CRTD), Technische Universität Dresden, Fetscherstr. 105, 01307 Dresden, Germany.
7
Center for Regenerative Therapies (CRTD), Technische Universität Dresden, Fetscherstr. 105, 01307 Dresden, Germany; Leibniz Institute of Polymer Research Dresden, Max Bergmann Center of Biomaterials Dresden, Hohe Str. 6, 01069 Dresden, Germany.
8
German Center for Neurodegenerative Diseases (DZNE) Dresden, Helmholtz Association, Arnoldstr. 18, 01307 Dresden, Germany; Center for Regenerative Therapies (CRTD), Technische Universität Dresden, Fetscherstr. 105, 01307 Dresden, Germany. Electronic address: caghan.kizil@dzne.de.

Abstract

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.

KEYWORDS:

3D starPEG-HEP hydrogel; Alzheimer's disease; amyloid-beta42; cortical neurogenesis; human neural stem cell; interleukin-4; kynurenic acid; neuroinflammation; plasticity; primary human astrocyte

PMID:
29974866
DOI:
10.1016/j.devcel.2018.06.005
[Indexed for MEDLINE]

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