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.
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.
复制标题
DOI：
10.3389/fimmu.2021.628156
复制
发表时间：
2021
影响因子：
7.3
通讯作者：
Lee DC
中科院分区：
文献类型：
--
作者：
Ma C;Hunt JB;Kovalenko A;Liang H;Selenica MB;Orr MB;Zhang B;Gensel JC;Feola DJ;Gordon MN;Morgan D;Bickford PC;Lee DC
脑髓样细胞，包括浸润性巨噬细胞和驻留的小胶质细胞，在响应和诱导神经退行性疾病如阿尔茨海默病（AD）中起重要作用。全基因组关联研究（GWAS）表明许多AD因果和风险基因在脑髓细胞中富集。通过精氨酸酶1（Arg 1）协调精氨酸代谢对于脑髓样细胞执行生物学功能至关重要，而精氨酸代谢失调会破坏它们。精氨酸代谢的改变被认为是AD的一种新的生物标志物途径。我们先前报道了使用溶菌酶M（LysM）启动子驱动缺失的髓样偏向细胞中Arg 1缺陷恶化淀粉样变性相关的神经病理学和行为障碍。然而，目前尚不清楚这些细胞中的Arg 1缺陷如何影响整个大脑以促进淀粉样变性。在此，我们的目的是确定淀粉样变性过程中LysM限制驱动的Arg 1缺陷如何在转录组水平影响基本的神经退行性通路。通过应用多种生物信息学工具和分析，我们发现淀粉样蛋白-β（Aβ）刺激自噬相关通路和髓样细胞炎症反应中的转录组特征。同时，淀粉样变性过程中髓样Arg 1缺陷促进了脂质代谢、髓鞘形成和髓样细胞迁移的基因特征。通过研究Aβ相关的胶质细胞转录组学特征，我们发现髓样Arg 1缺陷上调胶质细胞基因转录，与Aβ斑块负荷呈正相关。我们还观察到，Aβ优先激活疾病相关的小胶质细胞特征，以增加吞噬反应，而髓样Arg 1缺陷选择性地促进非吞噬的稳态小胶质细胞特征。这些转录组学研究结果表明，在淀粉样变性相关的正常和病理挑战过程中，适当的Arg 1功能发挥着关键作用。此外，了解控制Arg 1代谢的途径可能会提供新的治疗机会，以重新平衡免疫功能并改善小胶质细胞/巨噬细胞适应性。
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.
登录
查看更多内容
影响因子：
4.2
作者：
Duffy AM;Morales-Corraliza J;Bermudez-Hernandez KM;Schaner MJ;Magagna-Poveda A;Mathews PM;Scharfman HE
通讯作者：
Scharfman HE
影响因子：
5.5
作者：
Domingues HS;Portugal CC;Socodato R;Relvas JB
通讯作者：
Relvas JB
影响因子：
8
作者：
Cai, Wei;Dai, Xuejiao;Chen, Jun
通讯作者：
Chen, Jun
影响因子：
3
作者：
Clausen, BE;Burkhardt, C;Förster, I
通讯作者：
Förster, I
影响因子：
9.3
作者：
Colton CA;Mott RT;Sharpe H;Xu Q;Van Nostrand WE;Vitek MP
通讯作者：
Vitek MP