Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Frontiers in immunology, 2021-05, Vol.12, p.628156-628156

Ort / Verlag

Switzerland: Frontiers Media S.A

Erscheinungsjahr

2021

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 ( ) 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 deficiency in myeloid biased cells using lysozyme M (LysM) promoter-driven deletion worsened amyloidosis-related neuropathology and behavioral impairment. However, it remains unclear how deficiency in these cells impacts the whole brain to promote amyloidosis. Herein, we aim to determine how 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 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 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 deficiency selectively promoted homeostatic microglial signature that is non-phagocytic. These transcriptomic findings suggest a critical role for proper function during normal and pathological challenges associated with amyloidosis. Furthermore, understanding pathways that govern metabolism may provide new therapeutic opportunities to rebalance immune function and improve microglia/macrophage fitness.