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

doi:10.3389/fimmu.2021.628156

Abstract

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.

Highlights

Dysregulation of arginine metabolism has been recognized to impact neuropathology and neuroinflammation in Alzheimer’s disease (AD)
Together with our previous findings reporting that myeloid Arg1 insufficiency precipitates Ab deposition [39], the current transcriptomic analysis shows that myeloid Arg1 insufficiency activates Ab plaque-associated glial gene signatures to exacerbate neurodegeneration
We demonstrated that the APP transgene up-regulated pathways most related to autophagy, activated microglia, and AD causal risk, while Arg1 haploinsufficiency up-regulated pathways of lipid metabolism and myelination

Summary

Introduction

Dysregulation of arginine metabolism has been recognized to impact neuropathology and neuroinflammation in Alzheimer’s disease (AD). Recent metabolomics research in AD uncovered promising biomarker signatures associated with the deregulation of argininerelated pathways and polyamines in the blood and cerebral spinal fluid (CSF) [7,8,9,10]. The altered metabolism of arginine and arginase expression was confirmed in AD postmortem brains [11,12,13,14,15,16]. Human ARG1 has 43 mutations linked to ARG1 deficiency disorder, and a rare ARG2 variant was associated with a higher risk of AD [16, 17]. Increased arginine and altered Arg in the brain of animal models of aging and AD were reported, signifying a pivotal role for proper arginine metabolism in neurodegeneration [15, 18,19,20,21]

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