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iPSC-Derived Microglia for Modeling Human-Specific DAMP and PAMP Responses in the Context of Alzheimer’s Disease

Neuroinflammation in Alzheimer’s disease (AD) has been the focus for identifying targetable pathways for drug development. The role of amyloid beta (Aβ), a prototype of damage-associated molecular patterns (DAMPs), has been implicated in triggering an inflammatory response. As alpha7 nicotinic acety...

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Autores principales: Ihnatovych, Ivanna, Birkaya, Barbara, Notari, Emily, Szigeti, Kinga
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765962/
https://www.ncbi.nlm.nih.gov/pubmed/33352944
http://dx.doi.org/10.3390/ijms21249668
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author Ihnatovych, Ivanna
Birkaya, Barbara
Notari, Emily
Szigeti, Kinga
author_facet Ihnatovych, Ivanna
Birkaya, Barbara
Notari, Emily
Szigeti, Kinga
author_sort Ihnatovych, Ivanna
collection PubMed
description Neuroinflammation in Alzheimer’s disease (AD) has been the focus for identifying targetable pathways for drug development. The role of amyloid beta (Aβ), a prototype of damage-associated molecular patterns (DAMPs), has been implicated in triggering an inflammatory response. As alpha7 nicotinic acetylcholine receptor (α7 nAChR) binds Aβ with high affinity, α7 nAChR may play a role in Aβ-induced neuroinflammation. The conundrum of how α7 nAChR as the mediator of the cholinergic anti-inflammatory response may trigger an inflammatory response has not been resolved. CHRFAM7A, the uniquely human fusion gene between ULK4 and CHRNA7, is a negative regulator of α7 nAChR ionotropic function. To provide the human context, isogenic induced pluripotent stem cell (iPSC) lines were developed from CHRFAM7A null and carrier individuals by genome-editing the null line using TALENs to knock-in CHRFAM7A. In iPSC-derived microglia-like cells, CHRFAM7A mitigated Aβ uptake through the α7 nAChR. Despite the lower Aβ uptake, the presence of CHRFAM7A was associated with an innate immune response that was characterized by NF-κB activation and NF-κB target transcription (TNFA, IL6, and IL1B). LPS, a prototype PAMP, induced a heightened immune response in CHRFAM7A carriers. CHRFAM7A modified the dynamics of NF-κB translocation by prolonging its nuclear presence. CHRFAM7A modified the α7 nAChR metabotropic function, resulting in a human-specific innate immune response. This iPSC model provided an opportunity to elucidate the mechanism and establish high throughput screens.
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spelling pubmed-77659622020-12-28 iPSC-Derived Microglia for Modeling Human-Specific DAMP and PAMP Responses in the Context of Alzheimer’s Disease Ihnatovych, Ivanna Birkaya, Barbara Notari, Emily Szigeti, Kinga Int J Mol Sci Article Neuroinflammation in Alzheimer’s disease (AD) has been the focus for identifying targetable pathways for drug development. The role of amyloid beta (Aβ), a prototype of damage-associated molecular patterns (DAMPs), has been implicated in triggering an inflammatory response. As alpha7 nicotinic acetylcholine receptor (α7 nAChR) binds Aβ with high affinity, α7 nAChR may play a role in Aβ-induced neuroinflammation. The conundrum of how α7 nAChR as the mediator of the cholinergic anti-inflammatory response may trigger an inflammatory response has not been resolved. CHRFAM7A, the uniquely human fusion gene between ULK4 and CHRNA7, is a negative regulator of α7 nAChR ionotropic function. To provide the human context, isogenic induced pluripotent stem cell (iPSC) lines were developed from CHRFAM7A null and carrier individuals by genome-editing the null line using TALENs to knock-in CHRFAM7A. In iPSC-derived microglia-like cells, CHRFAM7A mitigated Aβ uptake through the α7 nAChR. Despite the lower Aβ uptake, the presence of CHRFAM7A was associated with an innate immune response that was characterized by NF-κB activation and NF-κB target transcription (TNFA, IL6, and IL1B). LPS, a prototype PAMP, induced a heightened immune response in CHRFAM7A carriers. CHRFAM7A modified the dynamics of NF-κB translocation by prolonging its nuclear presence. CHRFAM7A modified the α7 nAChR metabotropic function, resulting in a human-specific innate immune response. This iPSC model provided an opportunity to elucidate the mechanism and establish high throughput screens. MDPI 2020-12-18 /pmc/articles/PMC7765962/ /pubmed/33352944 http://dx.doi.org/10.3390/ijms21249668 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ihnatovych, Ivanna
Birkaya, Barbara
Notari, Emily
Szigeti, Kinga
iPSC-Derived Microglia for Modeling Human-Specific DAMP and PAMP Responses in the Context of Alzheimer’s Disease
title iPSC-Derived Microglia for Modeling Human-Specific DAMP and PAMP Responses in the Context of Alzheimer’s Disease
title_full iPSC-Derived Microglia for Modeling Human-Specific DAMP and PAMP Responses in the Context of Alzheimer’s Disease
title_fullStr iPSC-Derived Microglia for Modeling Human-Specific DAMP and PAMP Responses in the Context of Alzheimer’s Disease
title_full_unstemmed iPSC-Derived Microglia for Modeling Human-Specific DAMP and PAMP Responses in the Context of Alzheimer’s Disease
title_short iPSC-Derived Microglia for Modeling Human-Specific DAMP and PAMP Responses in the Context of Alzheimer’s Disease
title_sort ipsc-derived microglia for modeling human-specific damp and pamp responses in the context of alzheimer’s disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765962/
https://www.ncbi.nlm.nih.gov/pubmed/33352944
http://dx.doi.org/10.3390/ijms21249668
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