PUBLICATION

KYNA/Ahr Signaling Suppresses Neural Stem Cell Plasticity and Neurogenesis in Adult Zebrafish Model of Alzheimer's Disease

Authors
Siddiqui, T., Bhattarai, P., Popova, S., Cosacak, M.I., Sariya, S., Zhang, Y., Mayeux, R., Tosto, G., Kizil, C.
ID
ZDB-PUB-211025-54
Date
2021
Source
Cells   10(10): (Journal)
Registered Authors
Cosacak, Mehmet Ilyas, Kizil, Caghan
Keywords
Alzheimer’s disease, kynurenic acid, neural stem cell, neurogenesis, plasticity, proliferation, regeneration, transcriptome-wide association study, zebrafish
Datasets
GEO:GSE124162, GEO:GSE118577, GEO:GSE74326
MeSH Terms
  • Alzheimer Disease/pathology*
  • Alzheimer Disease/physiopathology*
  • Animals
  • Brain/metabolism
  • Brain/pathology
  • Cell Proliferation
  • Cohort Studies
  • Disease Models, Animal
  • Humans
  • Kynurenic Acid/metabolism*
  • Models, Biological
  • Neural Stem Cells/metabolism*
  • Neurogenesis*
  • Neuronal Plasticity*
  • Receptors, Aryl Hydrocarbon/metabolism*
  • Signal Transduction
  • Transcriptome/genetics
  • Zebrafish/metabolism*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
PubMed
34685728 Full text @ Cells
Abstract
Neurogenesis decreases in Alzheimer's disease (AD) patients, suggesting that restoring the normal neurogenic response could be a disease modifying intervention. To study the mechanisms of pathology-induced neuro-regeneration in vertebrate brains, zebrafish is an excellent model due to its extensive neural regeneration capacity. Here, we report that Kynurenic acid (KYNA), a metabolite of the amino acid tryptophan, negatively regulates neural stem cell (NSC) plasticity in adult zebrafish brain through its receptor, aryl hydrocarbon receptor 2 (Ahr2). The production of KYNA is suppressed after amyloid-toxicity through reduction of the levels of Kynurenine amino transferase 2 (KAT2), the key enzyme producing KYNA. NSC proliferation is enhanced by an antagonist for Ahr2 and is reduced with Ahr2 agonists or KYNA. A subset of Ahr2-expressing zebrafish NSCs do not express other regulatory receptors such as il4r or ngfra, indicating that ahr2-positive NSCs constitute a new subset of neural progenitors that are responsive to amyloid-toxicity. By performing transcriptome-wide association studies (TWAS) in three late onset Alzheimer disease (LOAD) brain autopsy cohorts, we also found that several genes that are components of KYNA metabolism or AHR signaling are differentially expressed in LOAD, suggesting a strong link between KYNA/Ahr2 signaling axis to neurogenesis in LOAD.
Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes