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

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.

The landscape of metabolic brain alterations in Alzheimer’s disease

“…The key enzyme in this pathway, arginase (ARG2) was positively associated with AD in our data. It catalyzes the conversion of arginine to ornithine with urea as a byproduct and has been previously linked to AD pathology due to its involvement in microglial activation and autophagy (66–68). Moreover, the reduction of urea levels through the inhibition of arginase (ARG2) has been suggested as a promising target in the context of AD (69).…”

Myelin repair in Alzheimer’s disease: a review of biological pathways and potential therapeutics

“…On the other hand, too much APP may also impair remyelination, as the same study also found decreased OLs in analogous human AD post-mortem tissues. A possible mechanism of myelin repair may be tied to Arginase 1 (Arg1) expression , as bulk RNA transcriptome analysis and cell type-profiling of APP mice demonstrated a significant association between insufficient Arg1 expression in myeloid cells, including OLs and other glial and phagocytic cells, and subsequent neurodegeneration and Aβ deposition [ 24 ]. Counterintuitively, Arg1 deficiency promotes OLs; more expectedly, it upregulates pro-inflammatory markers.…”

“…LPL deficiency has been thoroughly investigated as a possible contributing factor in the development of AD [25,[70][71][72]. LPL administration results in elevated cellular Arg1 levels [25], which has been previously implicated in myelin repair [24]. Lipid uptake may also be mediated by colony-stimulating factor 1 receptor, which, when inhibited, reduces microglia but potentially enhances the phagocytic capacity of remaining microglia, thus enabling remyelination [73].…”

The landscape of metabolic brain alterations in Alzheimer's disease

“…The key enzyme in this pathway, arginase (ARG2) was positively associated with AD in our data. It catalyzes the conversion of arginine to ornithine with urea as a byproduct and has been previously linked to AD pathology due to its involvement in microglial activation and autophagy 64–66 . Moreover, the reduction of urea levels through the inhibition of ARG2 has been suggested as a promising target in the context of AD 67 …”