Frontiers in Immunology (Jan 2021)
Arginase 1 Insufficiency Precipitates Amyloid-β Deposition and Hastens Behavioral Impairment in a Mouse Model of Amyloidosis
- Chao Ma,
- Chao Ma,
- Jerry B. Hunt,
- Jerry B. Hunt,
- Maj-Linda B. Selenica,
- Maj-Linda B. Selenica,
- Awa Sanneh,
- Leslie A. Sandusky-Beltran,
- Mallory Watler,
- Rana Daas,
- Andrii Kovalenko,
- Huimin Liang,
- Huimin Liang,
- Devon Placides,
- Chuanhai Cao,
- Xiaoyang Lin,
- Michael B. Orr,
- Bei Zhang,
- Bei Zhang,
- John C. Gensel,
- David J. Feola,
- Marcia N. Gordon,
- Dave Morgan,
- Paula C. Bickford,
- Paula C. Bickford,
- Paula C. Bickford,
- Daniel C. Lee,
- Daniel C. Lee
Affiliations
- Chao Ma
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
- Chao Ma
- Sanders-Brown Center on Aging, Department of Neuroscience, College of Medicine, University of Kentucky, Lexington, KY, United States
- Jerry B. Hunt
- Sanders-Brown Center on Aging, Department of Neuroscience, College of Medicine, University of Kentucky, Lexington, KY, United States
- Jerry B. Hunt
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, United States
- Maj-Linda B. Selenica
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, United States
- Maj-Linda B. Selenica
- Sanders-Brown Center on Aging, Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY, United States
- Awa Sanneh
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, United States
- Leslie A. Sandusky-Beltran
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, United States
- Mallory Watler
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, United States
- Rana Daas
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, United States
- Andrii Kovalenko
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, United States
- Huimin Liang
- Sanders-Brown Center on Aging, Department of Neuroscience, College of Medicine, University of Kentucky, Lexington, KY, United States
- Huimin Liang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, United States
- Devon Placides
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, United States
- Chuanhai Cao
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, United States
- Xiaoyang Lin
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, United States
- Michael B. Orr
- Spinal Cord and Brain Injury Research Center, Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, United States
- Bei Zhang
- Spinal Cord and Brain Injury Research Center, Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, United States
- Bei Zhang
- Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, Cornell University, New York, NY, United States
- John C. Gensel
- Spinal Cord and Brain Injury Research Center, Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, United States
- David J. Feola
- Department of Pharmacy Practice and Science, College of Pharmacy, University of Kentucky, Lexington, KY, United States
- Marcia N. Gordon
- Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States
- Dave Morgan
- Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States
- Paula C. Bickford
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
- Paula C. Bickford
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
- Paula C. Bickford
- 0Research Service, James A. Haley Veterans Affairs Hospital, Tampa, FL, United States
- Daniel C. Lee
- Sanders-Brown Center on Aging, Department of Neuroscience, College of Medicine, University of Kentucky, Lexington, KY, United States
- Daniel C. Lee
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, United States
- DOI
- https://doi.org/10.3389/fimmu.2020.582998
- Journal volume & issue
-
Vol. 11
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 Arg1fl/fl and LysMcreTg/+ 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.
Keywords
