Nucleoside reverse transcriptase inhibitors and Kamuvudines inhibit amyloid-β induced retinal pigmented epithelium degeneration.
Nucleoside reverse transcriptase inhibitors and Kamuvudines inhibit amyloid-β induced retinal pigmented epithelium degeneration.
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DOI：
10.1038/s41392-021-00537-z
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发表时间：
2021-04-14
影响因子：
39.3
通讯作者：
Ambati J
中科院分区：
文献类型：
--
作者：
Narendran S;Pereira F;Yerramothu P;Apicella I;Wang SB;Ambati K;Hirahara S;Kim Y;Ambati M;Ambati VL;Huang P;Varshney A;Nagasaka Y;Fukuda S;Baker KL;Marion KM;Deussing JM;Sadda SR;Gelfand BD;Ambati J
非纤维状淀粉样蛋白-β寡聚体（Aβ 0）是玻璃疣的主要成分，玻璃疣是年龄相关性黄斑变性（AMD）的特征性视网膜下色素上皮（RPE）细胞外沉积物，AMD是全球失明的常见原因。我们报告AβOs诱导RPE变性，这是地图状萎缩（GA）的临床标志，是目前无法治疗的威胁视力的AMD晚期。我们证明，Aβ O在体内诱导小鼠RPE中NLRP 3炎性体的活化，并且Aβ O诱导的RPE变性需要嘌呤能ATP受体P2 RX 7的表达，P2 RX 7是NLRP 3炎性体活化的上游介质。两类小分子炎性小体抑制剂-核苷类逆转录酶抑制剂（NRTI）及其抗逆转录病毒惰性修饰类似物Kamuvudines-均抑制Aβ Os诱导的RPE变性。这些发现明确了P2 RX 7和NLRP 3在AMD疾病相关模型中的重要性，并确定了炎性小体抑制剂作为GA的潜在治疗方法。
Nonfibrillar amyloid-β oligomers (AβOs) are a major component of drusen, the sub-retinal pigmented epithelium (RPE) extracellular deposits characteristic of age-related macular degeneration (AMD), a common cause of global blindness. We report that AβOs induce RPE degeneration, a clinical hallmark of geographic atrophy (GA), a vision-threatening late stage of AMD that is currently untreatable. We demonstrate that AβOs induce activation of the NLRP3 inflammasome in the mouse RPE in vivo and that RPE expression of the purinergic ATP receptor P2RX7, an upstream mediator of NLRP3 inflammasome activation, is required for AβO-induced RPE degeneration. Two classes of small molecule inflammasome inhibitors—nucleoside reverse transcriptase inhibitors (NRTIs) and their antiretrovirally inert modified analog Kamuvudines—both inhibit AβOs-induced RPE degeneration. These findings crystallize the importance of P2RX7 and NLRP3 in a disease-relevant model of AMD and identify inflammasome inhibitors as potential treatments for GA.
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影响因子：
4.4
作者：
Isas JM;Luibl V;Johnson LV;Kayed R;Wetzel R;Glabe CG;Langen R;Chen J
通讯作者：
Chen J
影响因子：
6.2
作者：
Deora, Vandana;Lee, John D.;Woodruff, Trent M.
通讯作者：
Woodruff, Trent M.
影响因子：
4.8
作者：
Johnson, AA;Ray, AS;Johnson, KA
通讯作者：
Johnson, KA
DOI：
10.1016/j.bbrc.2016.10.140
发表时间：
2017-01-01
影响因子：
3.1
作者：
Carver, Kyle A.;Lin, C. M.;Yang, Dongli
通讯作者：
Yang, Dongli
影响因子：
4.4
作者：
Aredo, Bogale;Li, Tao;Ufret-Vincenty, Rafael L.
通讯作者：
Ufret-Vincenty, Rafael L.