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

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...

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Main Authors: Tohid Siddiqui, Prabesh Bhattarai, Stanislava Popova, Mehmet Ilyas Cosacak, Sanjeev Sariya, Yixin Zhang, Richard Mayeux, Giuseppe Tosto, Caghan Kizil
Format: Article
Language:English
Published: MDPI AG 2021-10-01
Series:Cells
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Online Access:https://www.mdpi.com/2073-4409/10/10/2748
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author Tohid Siddiqui
Prabesh Bhattarai
Stanislava Popova
Mehmet Ilyas Cosacak
Sanjeev Sariya
Yixin Zhang
Richard Mayeux
Giuseppe Tosto
Caghan Kizil
author_facet Tohid Siddiqui
Prabesh Bhattarai
Stanislava Popova
Mehmet Ilyas Cosacak
Sanjeev Sariya
Yixin Zhang
Richard Mayeux
Giuseppe Tosto
Caghan Kizil
author_sort Tohid Siddiqui
collection DOAJ
description 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 <i>il4r</i> or <i>ngfra</i>, indicating that <i>ahr2</i>-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.
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spelling doaj.art-0f577cd1263a49538ea97d57cc823b422023-11-22T17:48:32ZengMDPI AGCells2073-44092021-10-011010274810.3390/cells10102748KYNA/Ahr Signaling Suppresses Neural Stem Cell Plasticity and Neurogenesis in Adult Zebrafish Model of Alzheimer’s DiseaseTohid Siddiqui0Prabesh Bhattarai1Stanislava Popova2Mehmet Ilyas Cosacak3Sanjeev Sariya4Yixin Zhang5Richard Mayeux6Giuseppe Tosto7Caghan Kizil8German Center for Neurodegenerative Diseases (DZNE) within Helmholtz Association, Tatzberg 41, 01307 Dresden, GermanyGerman Center for Neurodegenerative Diseases (DZNE) within Helmholtz Association, Tatzberg 41, 01307 Dresden, GermanyGerman Center for Neurodegenerative Diseases (DZNE) within Helmholtz Association, Tatzberg 41, 01307 Dresden, GermanyGerman Center for Neurodegenerative Diseases (DZNE) within Helmholtz Association, Tatzberg 41, 01307 Dresden, GermanyThe Department of Neurology, The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USAB-CUBE, Center for Molecular Bioengineering, TU Dresden, Tatzberg 41, 01307 Dresden, GermanyThe Department of Neurology, The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USAThe Department of Neurology, The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical Center, 630 West 168th Street, New York, NY 10032, USAGerman Center for Neurodegenerative Diseases (DZNE) within Helmholtz Association, Tatzberg 41, 01307 Dresden, GermanyNeurogenesis 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 <i>il4r</i> or <i>ngfra</i>, indicating that <i>ahr2</i>-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.https://www.mdpi.com/2073-4409/10/10/2748zebrafishAlzheimer’s diseaseneurogenesisregenerationneural stem cellkynurenic acid
spellingShingle Tohid Siddiqui
Prabesh Bhattarai
Stanislava Popova
Mehmet Ilyas Cosacak
Sanjeev Sariya
Yixin Zhang
Richard Mayeux
Giuseppe Tosto
Caghan Kizil
KYNA/Ahr Signaling Suppresses Neural Stem Cell Plasticity and Neurogenesis in Adult Zebrafish Model of Alzheimer’s Disease
Cells
zebrafish
Alzheimer’s disease
neurogenesis
regeneration
neural stem cell
kynurenic acid
title KYNA/Ahr Signaling Suppresses Neural Stem Cell Plasticity and Neurogenesis in Adult Zebrafish Model of Alzheimer’s Disease
title_full KYNA/Ahr Signaling Suppresses Neural Stem Cell Plasticity and Neurogenesis in Adult Zebrafish Model of Alzheimer’s Disease
title_fullStr KYNA/Ahr Signaling Suppresses Neural Stem Cell Plasticity and Neurogenesis in Adult Zebrafish Model of Alzheimer’s Disease
title_full_unstemmed KYNA/Ahr Signaling Suppresses Neural Stem Cell Plasticity and Neurogenesis in Adult Zebrafish Model of Alzheimer’s Disease
title_short KYNA/Ahr Signaling Suppresses Neural Stem Cell Plasticity and Neurogenesis in Adult Zebrafish Model of Alzheimer’s Disease
title_sort kyna ahr signaling suppresses neural stem cell plasticity and neurogenesis in adult zebrafish model of alzheimer s disease
topic zebrafish
Alzheimer’s disease
neurogenesis
regeneration
neural stem cell
kynurenic acid
url https://www.mdpi.com/2073-4409/10/10/2748
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