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

Authors

Chao Ma, University of Kentucky
Jerry B. Hunt, University of KentuckyFollow
Maj-Linda B. Selenica, University of KentuckyFollow
Awa Sanneh, University of South Florida
Leslie A. Sandusky-Beltran, University of South Florida
Mallory Watler, University of South Florida
Rana Daas, University of South Florida
Andrii Kovalenko, University of South Florida
Huimin Liang, University of KentuckyFollow
Devon Placides, University of South Florida
Chuanhai Cao, University of South Florida
Xiaoyang Lin, University of South Florida
Michael B. Orr, University of KentuckyFollow
Bei Zhang, University of Kentucky
John C. Gensel, University of KentuckyFollow
David J. Feola, University of KentuckyFollow
Marcia N. Gordon, Michigan State University
Dave Morgan, Michigan State University
Paula C. Bickford, University of South Florida
Daniel C. Lee, University of KentuckyFollow

Abstract

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.

Document Type

Article

Publication Date

1-14-2021

Notes/Citation Information

Published in Frontiers in Immunology, v. 11, article 582998.

© 2021 Ma, Hunt, Selenica, Sanneh, Sandusky-Beltran, Watler, Daas, Kovalenko, Liang, Placides, Cao, Lin, Orr, Zhang, Gensel, Feola, Gordon, Morgan, Bickford and Lee.

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.

Digital Object Identifier (DOI)

https://doi.org/10.3389/fimmu.2020.582998

Funding Information

Funding for this work is provided by the NIH NIA R21-AG055996 (to DL), NIA R01-AG054559 (to DL), NIA R01-AG051500 (to DM), NINDS R01-NS091582 (to JG), NIAID R01-AI095307 (to DF), Alzheimer’s Association AARGD-16-441534 (to DL) and MNIRGD-12-242665 (to DL), Florida Department of Health Ed and Ethel Moore Alzheimer’s disease (8AZ30) (to DL, PB), and IKBX004214 (to PB). CM is awarded by USF Health Neuroscience Institute Dorothy Benjamin Graduate Fellowship in Alzheimer’s Disease.

Related Content

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Description of the supplementary file:

Primary macrophages with Arg1 deficiency showed reduced arginase activity and failed to improve neuron viability. (A) In macrophage arginase activity assay, primary macrophages isolated from both nTg/Arg1^+/+ mice (wild type control) and nTg/Arg1^fl/fl mice (Arg1^flox transgenic control) showed increased arginase activity post IL-4 treatment with or without LPS (p < 0.0001); however, macrophages of nTg/Arg1^fl/fl/LysMcre^Tg/+ mice did not induce arginase activity in both conditions. In addition, in IL-4 treatment with or without LPS co-stimulation, primary macrophages isolated from nTg/Arg1^fl/fl/LysMcre^Tg/+ mice showed decreased arginase activity compared to macrophages from either nTg/Arg1^+/+ mice (p < 0.0001) or nTg/Arg1^fl/fl mice (p < 0.0001). n = 3 independent replicates from three independent biological replication experiments. (B) In measuring Neuro-2a viability using macrophage conditioned medium (MCM), neuroprotection drug azithromycin (AZM) co-incubation with LPS/IFN-γ increased neuron viability compared to LPS/IFN-γ stimulation, a phenomenon only observed using MCM from nTg/Arg1^+/+ mice (p < 0.0001), but not in nTg/Arg1^fl/fl/LysMcre^Tg/+ mice. In addition, AZM co-incubation with LPS/IL-4 showed increased trend in neuron viability than LPS/IL-4 stimulation using MCM from nTg/Arg1^+/+ mice (p = 0.051), but not in nTg/Arg1^fl/fl/LysMcre^Tg/+ mice. n = 10 independent replicates from three independent biological replication experiments. ****, p < 0.0001; n.s. (not significant), p > 0.05. Two-way ANOVA followed by multiple comparisons with Dunnett’s or Sidak’s post-hoc tests. Values represent mean ± SEM.

Repository Citation

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.; and Lee, Daniel C., "Arginase 1 Insufficiency Precipitates Amyloid-β Deposition and Hastens Behavioral Impairment in a Mouse Model of Amyloidosis" (2021). Sanders-Brown Center on Aging Faculty Publications. 158.
https://uknowledge.uky.edu/sbcoa_facpub/158