Myeloid Arginase 1 Insufficiency Exacerbates Amyloid-β Associated Neurodegenerative Pathways and Glial Signatures in a Mouse Model of Alzheimer’s Disease: A Targeted Transcriptome Analysis

Chao Ma, Jerry B. Hunt, Andrii Kovalenko, Huimin Liang, Maj Linda B. Selenica, Michael B. Orr, Bei Zhang, John C. Gensel, David J. Feola, Marcia N. Gordon, Dave Morgan, Paula C. Bickford, Daniel C. Lee

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Brain myeloid cells, include infiltrating macrophages and resident microglia, play an essential role in responding to and inducing neurodegenerative diseases, such as Alzheimer’s disease (AD). Genome-wide association studies (GWAS) implicate many AD casual and risk genes enriched in brain myeloid cells. Coordinated arginine metabolism through arginase 1 (Arg1) is critical for brain myeloid cells to perform biological functions, whereas dysregulated arginine metabolism disrupts them. Altered arginine metabolism is proposed as a new biomarker pathway for AD. We previously reported Arg1 deficiency in myeloid biased cells using lysozyme M (LysM) promoter-driven deletion worsened amyloidosis-related neuropathology and behavioral impairment. However, it remains unclear how Arg1 deficiency in these cells impacts the whole brain to promote amyloidosis. Herein, we aim to determine how Arg1 deficiency driven by LysM restriction during amyloidosis affects fundamental neurodegenerative pathways at the transcriptome level. By applying several bioinformatic tools and analyses, we found that amyloid-β (Aβ) stimulated transcriptomic signatures in autophagy-related pathways and myeloid cells’ inflammatory response. At the same time, myeloid Arg1 deficiency during amyloidosis promoted gene signatures of lipid metabolism, myelination, and migration of myeloid cells. Focusing on Aβ associated glial transcriptomic signatures, we found myeloid Arg1 deficiency up-regulated glial gene transcripts that positively correlated with Aβ plaque burden. We also observed that Aβ preferentially activated disease-associated microglial signatures to increase phagocytic response, whereas myeloid Arg1 deficiency selectively promoted homeostatic microglial signature that is non-phagocytic. These transcriptomic findings suggest a critical role for proper Arg1 function during normal and pathological challenges associated with amyloidosis. Furthermore, understanding pathways that govern Arg1 metabolism may provide new therapeutic opportunities to rebalance immune function and improve microglia/macrophage fitness.

Original languageEnglish
Article number628156
JournalFrontiers in Immunology
StatePublished - May 11 2021

Bibliographical note

Funding Information:
Funding for this work was provided by the NIH R21-AG055996 (to DL), R01-AG054559 (to DL), R01-AG051500 (to DM), R01-NS091582 (to JG), 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 and PB), and IKBX004214 (to PB). CM was awarded by USF Health Neuroscience Institute Dorothy Benjamin Graduate Fellowship in Alzheimer’s Disease.

Funding Information:
PB was affiliated with James A. Haley Veterans Affairs Hospital and would like to acknowledge this affiliation.

Publisher Copyright:
© Copyright © 2021 Ma, Hunt, Kovalenko, Liang, Selenica, Orr, Zhang, Gensel, Feola, Gordon, Morgan, Bickford and Lee.


  • APP Tg2576
  • amyloidosis
  • arginine metabolism
  • infiltrating macrophage
  • microglia
  • nCounter technology
  • neurodegeneration
  • neuroinflammation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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