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

Research output: Contribution to journalResearch articleContributedpeer-review



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.


Original languageEnglish
Pages (from-to)85-101.e8
JournalDevelopmental Cell
Issue number1
Publication statusPublished - 2 Jul 2018

External IDs

PubMed 29974866
Scopus 85048825554
ORCID /0000-0001-5624-1717/work/162347110
ORCID /0000-0003-0189-3448/work/162347620
ORCID /0000-0002-6669-4995/work/162348646


Sustainable Development Goals


  • Adult, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Peptides/metabolism, Animals, Brain/metabolism, Cell Plasticity/physiology, Cell Proliferation/physiology, Cells, Cultured, Disease Models, Animal, Female, Humans, Interleukin-4/metabolism, Kynurenic Acid/metabolism, Male, Mice, Mice, Transgenic, Middle Aged, Neural Stem Cells/cytology, Neurogenesis/physiology, Neurons/cytology, Transaminases/metabolism, Transcriptional Activation/genetics, Young Adult