Arginase 1 Insufficiency Precipitates Amyloid-β Deposition and Hastens Behavioral Impairment in a Mouse Model of Amyloidosis.
Arginase 1 Insufficiency Precipitates Amyloid-β Deposition and Hastens Behavioral Impairment in a Mouse Model of Amyloidosis.
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DOI：
10.3389/fimmu.2020.582998
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发表时间：
2020
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;Selenica MB;Sanneh A;Sandusky-Beltran LA;Watler M;Daas R;Kovalenko A;Liang H;Placides D;Cao C;Lin X;Orr MB;Zhang B;Gensel JC;Feola DJ;Gordon MN;Morgan D;Bickford PC;Lee DC
阿尔茨海默病(AD)包括几个特征，包括淀粉样蛋白(Aβ，Aβ)沉积、tau神经病理、炎症和记忆障碍。由于衰老和其他AD危险因素，大脑代谢变得不耦合，最终导致蛋白质清除和聚集受损。越来越多的证据表明精氨酸代谢在阿尔茨海默病中的作用，精氨酸酶是神经元和胶质细胞中的关键酶，能够消耗精氨酸并产生鸟氨酸和多胺。然而，目前尚不清楚髓系细胞中精氨酸酶1(Arg1)的减少是否会影响淀粉样变性。在这里，我们用Arg1fl/fl和LysMcreTg/+小鼠与APP Tg2576小鼠杂交，通过半合子缺失的方式在髓系细胞中产生Arg1单倍体不足。我们的数据表明，Arg1单倍体不足促进了Aβ的沉积，加剧了一些行为障碍，并减少了参与雷帕霉素复合体1信号转导和自噬的刺激物-RAG复合体成分。此外，在体外，Arg1抑制和补充精氨酸都会损害小胶质细胞的吞噬功能。这些数据表明，髓系细胞中Arg1和精氨酸代谢的适当功能对于限制淀粉样变性仍然是必不可少的。
Alzheimer’s disease (AD) includes several hallmarks comprised of amyloid-β (Aβ) deposition, tau neuropathology, inflammation, and memory impairment. Brain metabolism becomes uncoupled due to aging and other AD risk factors, which ultimately lead to impaired protein clearance and aggregation. Increasing evidence indicates a role of arginine metabolism in AD, where arginases are key enzymes in neurons and glia capable of depleting arginine and producing ornithine and polyamines. However, currently, it remains unknown if the reduction of arginase 1 (Arg1) in myeloid cell impacts amyloidosis. Herein, we produced haploinsufficiency of Arg1 by the hemizygous deletion in myeloid cells using Arg1fl/fl and LysMcreTg/+ mice crossed with APP Tg2576 mice. Our data indicated that Arg1 haploinsufficiency promoted Aβ deposition, exacerbated some behavioral impairment, and decreased components of Ragulator-Rag complex involved in mechanistic target of rapamycin complex 1 (mTORC1) signaling and autophagy. Additionally, Arg1 repression and arginine supplementation both impaired microglial phagocytosis in vitro. These data suggest that proper function of Arg1 and arginine metabolism in myeloid cells remains essential to restrict amyloidosis.
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影响因子：
30.8
作者：
Haney MS;Bohlen CJ;Morgens DW;Ousey JA;Barkal AA;Tsui CK;Ego BK;Levin R;Kamber RA;Collins H;Tucker A;Li A;Vorselen D;Labitigan L;Crane E;Boyle E;Jiang L;Chan J;Rincón E;Greenleaf WJ;Li B;Snyder MP;Weissman IL;Theriot JA;Collins SR;Barres BA;Bassik MC
通讯作者：
Bassik MC
影响因子：
3.7
作者：
Das P;Kang SG;Temple S;Belfort G
通讯作者：
Belfort G
影响因子：
8
作者：
Cai, Wei;Dai, Xuejiao;Chen, Jun
通讯作者：
Chen, Jun
影响因子：
3.7
作者：
Graham, Stewart F.;Chevallier, Olivier P.;Green, Brian D.
通讯作者：
Green, Brian D.
影响因子：
3
作者：
Clausen, BE;Burkhardt, C;Förster, I
通讯作者：
Förster, I