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Arginase 1 Insufficiency Precipitates Amyloid-β Deposition and Hastens Behavioral Impairment in a Mouse Model of Amyloidosis

Alzheimer’s disease (AD) includes several hallmarks comprised of amyloid-β (Aβ) deposition, tau neuropathology, inflammation, and memory impairment. Brain metabolism becomes uncoupled due to aging and other AD risk factors, which ultimately lead to impaired protein clearance and aggregation. Increas...

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Autores principales: Ma, Chao, Hunt, Jerry B., Selenica, Maj-Linda B., Sanneh, Awa, Sandusky-Beltran, Leslie A., Watler, Mallory, Daas, Rana, Kovalenko, Andrii, Liang, Huimin, Placides, Devon, Cao, Chuanhai, Lin, Xiaoyang, Orr, Michael B., Zhang, Bei, Gensel, John C., Feola, David J., Gordon, Marcia N., Morgan, Dave, Bickford, Paula C., Lee, Daniel C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840571/
https://www.ncbi.nlm.nih.gov/pubmed/33519806
http://dx.doi.org/10.3389/fimmu.2020.582998
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author Ma, Chao
Hunt, Jerry B.
Selenica, Maj-Linda B.
Sanneh, Awa
Sandusky-Beltran, Leslie A.
Watler, Mallory
Daas, Rana
Kovalenko, Andrii
Liang, Huimin
Placides, Devon
Cao, Chuanhai
Lin, Xiaoyang
Orr, Michael B.
Zhang, Bei
Gensel, John C.
Feola, David J.
Gordon, Marcia N.
Morgan, Dave
Bickford, Paula C.
Lee, Daniel C.
author_facet Ma, Chao
Hunt, Jerry B.
Selenica, Maj-Linda B.
Sanneh, Awa
Sandusky-Beltran, Leslie A.
Watler, Mallory
Daas, Rana
Kovalenko, Andrii
Liang, Huimin
Placides, Devon
Cao, Chuanhai
Lin, Xiaoyang
Orr, Michael B.
Zhang, Bei
Gensel, John C.
Feola, David J.
Gordon, Marcia N.
Morgan, Dave
Bickford, Paula C.
Lee, Daniel C.
author_sort Ma, Chao
collection PubMed
description Alzheimer’s disease (AD) includes several hallmarks comprised of amyloid-β (Aβ) deposition, tau neuropathology, inflammation, and memory impairment. Brain metabolism becomes uncoupled due to aging and other AD risk factors, which ultimately lead to impaired protein clearance and aggregation. Increasing evidence indicates a role of arginine metabolism in AD, where arginases are key enzymes in neurons and glia capable of depleting arginine and producing ornithine and polyamines. However, currently, it remains unknown if the reduction of arginase 1 (Arg1) in myeloid cell impacts amyloidosis. Herein, we produced haploinsufficiency of Arg1 by the hemizygous deletion in myeloid cells using Arg1(fl/fl) and LysMcre(Tg/+) mice crossed with APP Tg2576 mice. Our data indicated that Arg1 haploinsufficiency promoted Aβ deposition, exacerbated some behavioral impairment, and decreased components of Ragulator-Rag complex involved in mechanistic target of rapamycin complex 1 (mTORC1) signaling and autophagy. Additionally, Arg1 repression and arginine supplementation both impaired microglial phagocytosis in vitro. These data suggest that proper function of Arg1 and arginine metabolism in myeloid cells remains essential to restrict amyloidosis.
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spelling pubmed-78405712021-01-29 Arginase 1 Insufficiency Precipitates Amyloid-β Deposition and Hastens Behavioral Impairment in a Mouse Model of Amyloidosis Ma, Chao Hunt, Jerry B. Selenica, Maj-Linda B. Sanneh, Awa Sandusky-Beltran, Leslie A. Watler, Mallory Daas, Rana Kovalenko, Andrii Liang, Huimin Placides, Devon Cao, Chuanhai Lin, Xiaoyang Orr, Michael B. Zhang, Bei Gensel, John C. Feola, David J. Gordon, Marcia N. Morgan, Dave Bickford, Paula C. Lee, Daniel C. Front Immunol Immunology Alzheimer’s disease (AD) includes several hallmarks comprised of amyloid-β (Aβ) deposition, tau neuropathology, inflammation, and memory impairment. Brain metabolism becomes uncoupled due to aging and other AD risk factors, which ultimately lead to impaired protein clearance and aggregation. Increasing evidence indicates a role of arginine metabolism in AD, where arginases are key enzymes in neurons and glia capable of depleting arginine and producing ornithine and polyamines. However, currently, it remains unknown if the reduction of arginase 1 (Arg1) in myeloid cell impacts amyloidosis. Herein, we produced haploinsufficiency of Arg1 by the hemizygous deletion in myeloid cells using Arg1(fl/fl) and LysMcre(Tg/+) mice crossed with APP Tg2576 mice. Our data indicated that Arg1 haploinsufficiency promoted Aβ deposition, exacerbated some behavioral impairment, and decreased components of Ragulator-Rag complex involved in mechanistic target of rapamycin complex 1 (mTORC1) signaling and autophagy. Additionally, Arg1 repression and arginine supplementation both impaired microglial phagocytosis in vitro. These data suggest that proper function of Arg1 and arginine metabolism in myeloid cells remains essential to restrict amyloidosis. Frontiers Media S.A. 2021-01-14 /pmc/articles/PMC7840571/ /pubmed/33519806 http://dx.doi.org/10.3389/fimmu.2020.582998 Text en Copyright © 2021 Ma, Hunt, Selenica, Sanneh, Sandusky-Beltran, Watler, Daas, Kovalenko, Liang, Placides, Cao, Lin, Orr, Zhang, Gensel, Feola, Gordon, Morgan, Bickford and Lee http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Ma, Chao
Hunt, Jerry B.
Selenica, Maj-Linda B.
Sanneh, Awa
Sandusky-Beltran, Leslie A.
Watler, Mallory
Daas, Rana
Kovalenko, Andrii
Liang, Huimin
Placides, Devon
Cao, Chuanhai
Lin, Xiaoyang
Orr, Michael B.
Zhang, Bei
Gensel, John C.
Feola, David J.
Gordon, Marcia N.
Morgan, Dave
Bickford, Paula C.
Lee, Daniel C.
Arginase 1 Insufficiency Precipitates Amyloid-β Deposition and Hastens Behavioral Impairment in a Mouse Model of Amyloidosis
title Arginase 1 Insufficiency Precipitates Amyloid-β Deposition and Hastens Behavioral Impairment in a Mouse Model of Amyloidosis
title_full Arginase 1 Insufficiency Precipitates Amyloid-β Deposition and Hastens Behavioral Impairment in a Mouse Model of Amyloidosis
title_fullStr Arginase 1 Insufficiency Precipitates Amyloid-β Deposition and Hastens Behavioral Impairment in a Mouse Model of Amyloidosis
title_full_unstemmed Arginase 1 Insufficiency Precipitates Amyloid-β Deposition and Hastens Behavioral Impairment in a Mouse Model of Amyloidosis
title_short Arginase 1 Insufficiency Precipitates Amyloid-β Deposition and Hastens Behavioral Impairment in a Mouse Model of Amyloidosis
title_sort arginase 1 insufficiency precipitates amyloid-β deposition and hastens behavioral impairment in a mouse model of amyloidosis
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840571/
https://www.ncbi.nlm.nih.gov/pubmed/33519806
http://dx.doi.org/10.3389/fimmu.2020.582998
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