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Cited by 24Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

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

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Ma, Chao, Hunt, Jerry B., Selenica, Maj-Linda B., Sanneh, Awa, Sandusky-Beltran, Leslie A., Watler, Mallory, Daas, Rana, Kovalenko, Andrii +12 more·2021·Frontiers in Immunology
DOI 10.3389/fimmu.2020.582998PMC PMC7840571
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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.

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  • Increased iNOS and decreased Arg-1 found in MG-AD are consistent with a pro-inflammatory status.

    “The increased iNOS and decreased Arg-1 found in MG-AD are consistent with a pro-inflammatory status, as previously documented in AD microglia [105,106].”

    From Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease (2022) · cites this paper as [105]

    The Results section on microglial activation (page unavailable) reports that experimentally induced Arg1 insufficiency increased microglial activation in an amyloidosis mouse model. The Discussion (page unavailable) also links Arg1 insufficiency to neuroinflammation, but the paper does not document increased iNOS alongside decreased Arg1 in AD microglia; its Arg1 reduction was experimentally induced. (LLM, conf=0.84)

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Cited by

Sorted by citations

Authors
Ma, C., Hunt, J. B., Selenica, M.-L. B., Sanneh, A., Sandusky-Beltran, L. A., Watler, M., Daas, R., Kovalenko, A., Liang, H., Placides, D., Cao, C., Lin, X., Orr, M. B., Zhang, B., Gensel, J. C., Feola, D. J., Gordon, M. N., Morgan, D., Bickford, P. C., & Lee, D. C.
Affiliations
  • University of Kentucky (US)
  • University of South Florida (US)
  • Michigan State University (US)
Corresponding author
Lee, Daniel C.
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2021-01-14
Volume
11
Pages
582998-582998
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2020.582998
PMC
PMC7840571
OpenAlex
W3120998555
Cited by
24
References
17
Citations by year
2026: 3 · 2025: 2 · 2024: 4 · 2023: 2 · 2022: 8 · 2021: 5
FWCI
2.98
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UKnowledge (University of Kentucky) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Veterans Affairs (IK6 BX004214)
  • Alzheimer's Association (MNIRGD-12-242665, AARGD-16-441534)
  • Florida Department of Health
  • National Institutes of Health (NIAID-R01)
  • National Institute on Aging (R21AG055996, R01AG054559, R01AG051500, AG 051500)
  • National Institute of Allergy and Infectious Diseases (R01AI095307)
  • National Institute of Neurological Disorders and Stroke (F31NS110264, NS091582, R01NS091582)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
arginase-1, arginine metabolism, amyloid-beta deposition, Alzheimer's disease, amyloidosis, myeloid cells, microglia, haploinsufficiency, mTORC1 signaling, autophagy, arginine supplementation, microglial phagocytosis, behavioral impairment
MeSH terms
Mechanistic Target of Rapamycin Complex 1, Amyloidosis, Animals, Arginase, Autophagy, Behavior, Animal, Disease Models, Animal, Humans, Mice, Transgenic, Signal Transduction, Amyloid beta-Peptides, Attention Deficit and Disruptive Behavior Disorders, Neurogenic Inflammation, Myeloid Cells, Mice

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