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

Signal Transduction
Animals
Transcriptome/genetics
Alzheimer Disease/pathology*
Alzheimer Disease/physiopathology*
Brain/metabolism
Brain/pathology
Zebrafish Proteins/genetics
Zebrafish Proteins/metabolism
Neuronal Plasticity*
Receptors, Aryl Hydrocarbon/metabolism*
Zebrafish/metabolism*
Neurogenesis*
Cell Proliferation
Humans
Models, Biological
Disease Models, Animal
Neural Stem Cells/metabolism*
Kynurenic Acid/metabolism*
Cohort Studies

(all 20)

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

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
cyp1b1	AB	chemical treatment by injection: beta-naphthoflavone	Adult	forebrain	RTPCR	Figure 2
cyp1b1	AB	chemical treatment by injection: aryl hydrocarbon receptor antagonist	Adult	forebrain	RTPCR	Figure 2
cyp1b1	AB	standard conditions	Adult	forebrain	RTPCR	Figure 2
cyp1b1	AB	chemical treatment by injection: kynurenic acid	Adult	forebrain	RTPCR	Figure 2
cyp1b1	AB	chemical treatment by injection: amyloid-beta polypeptide 42	Adult	forebrain	RTPCR	Figure 2
cyp1b1	AB	standard conditions	Adult	forebrain ventricle anatomical region	ISH	Figure 1
cyp1b1	AB	chemical treatment by injection: aryl hydrocarbon receptor antagonist	Adult	forebrain ventricle anatomical region	ISH	Figure 2
cyp1b1	AB	chemical treatment by injection: amyloid-beta polypeptide 42	Adult	forebrain ventricle anatomical region	ISH	Figure 2
cyp1b1	AB	chemical treatment by injection: beta-naphthoflavone	Adult	forebrain ventricle anatomical region	ISH	Figure 2
cyp1b1	AB	chemical treatment by injection: kynurenic acid	Adult	forebrain ventricle anatomical region	ISH	Figure 2

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
AB	chemical treatment by injection: amyloid-beta polypeptide 42	Adult	forebrain ventricle anatomical region cyp1b1 expression decreased amount, abnormal	Figure 2
AB	chemical treatment by injection: amyloid-beta polypeptide 42	Adult	forebrain ventricle anatomical region AB1-kat2 labeling decreased amount, abnormal	Figure 1
AB	chemical treatment by injection: amyloid-beta polypeptide 42	Adult	glial cell (sensu Vertebrata) cell population proliferation increased occurrence, abnormal	Figure 3
AB	chemical treatment by injection: amyloid-beta polypeptide 42, chemical treatment by injection: beta-naphthoflavone	Adult	glial cell (sensu Vertebrata) cell population proliferation normal occurrence, normal	Figure 4
AB	chemical treatment by injection: aryl hydrocarbon receptor antagonist	Adult	forebrain ventricle anatomical region cyp1b1 expression decreased amount, abnormal	Figure 2
AB	chemical treatment by injection: aryl hydrocarbon receptor antagonist	Adult	glial cell (sensu Vertebrata) cell population proliferation increased occurrence, abnormal	Figure 3
AB	chemical treatment by injection: beta-naphthoflavone	Adult	forebrain cyp1b1 expression increased amount, abnormal	Figure 2
AB	chemical treatment by injection: beta-naphthoflavone	Adult	forebrain ventricle anatomical region cyp1b1 expression increased amount, abnormal	Figure 2
AB	chemical treatment by injection: beta-naphthoflavone	Adult	glial cell (sensu Vertebrata) cell population proliferation decreased occurrence, abnormal	Figure 3
AB	chemical treatment by injection: aryl hydrocarbon receptor antagonist, chemical treatment by injection: beta-naphthoflavone	Adult	glial cell (sensu Vertebrata) cell population proliferation normal occurrence, normal	Figure 4

1 - 10 of 16

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
y83Tg	Tg(her4.3:EGFP)	Transgenic Insertion

Human Disease / Model

Human Disease	Fish	Conditions	Evidence
amyloidosis	y83Tg (AB)	chemical treatment by injection: amyloid-beta polypeptide 42	TAS

Sequence Targeting Reagents

Fish

Fish
AB
y83Tg (AB)

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP

Mapping

Siddiqui et al., 2021 ZDB-PUB-211025-54 PMID:34685728

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

Siddiqui et al., 2021

ZDB-PUB-211025-54
PMID:34685728