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- (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. Inc...

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Veröffentlicht in:Frontiers in immunology 2021-01, Vol.11, p.582998-582998
Hauptverfasser: 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
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Sprache:eng
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Zusammenfassung:Alzheimer's disease (AD) includes several hallmarks comprised of amyloid- (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 ( in myeloid cell impacts amyloidosis. Herein, we produced haploinsufficiency of by the hemizygous deletion in myeloid cells using and mice crossed with Tg2576 mice. Our data indicated that 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, repression and arginine supplementation both impaired microglial phagocytosis . These data suggest that proper function of and arginine metabolism in myeloid cells remains essential to restrict amyloidosis.
ISSN:1664-3224
1664-3224
DOI:10.3389/fimmu.2020.582998