The ABC transporter A7 modulates neuroinflammation via NLRP3 inflammasome in Alzheimer's disease mice.

IF 7.9 1区 医学 Q1 CLINICAL NEUROLOGY
Irene Santos-García, Pablo Bascuñana, Mirjam Brackhan, María Villa, Ivan Eiriz, Thomas Brüning, Jens Pahnke
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引用次数: 0

Abstract

Background: Specific genetic variants in the ATP-binding cassette transporter A7 locus (ABCA7) are associated with an increased risk of Alzheimer's disease (AD). ABCA7 transports lipids from/across cell membranes, regulates Aβ peptide processing and clearance, and modulates microglial and T-cell functions to maintain immune homeostasis in the brain. During AD pathogenesis, neuroinflammation is one of the key mechanisms involved. Therefore, we wanted to investigate the specific role of ABCA7 in microglial activation via the NLRP3 inflammasome.

Methods: We developed the first humanized, Cre-inducible ABCA7flx knock-in mouse model, crossbred it with the APPPS1-21 β-amyloidosis model, and generated constitutive ABCA7ko and microglia Cx3cr1-specific conditional ABCA7ko AD mice. The role of ABCA7 was analyzed using histological, biochemical, molecular and mass spectrometry methods.

Results: Constitutive knockout of the Abca7 gene in APPPS1 mice increased the levels of Aβ42 and the number of IBA1+ (microglia) and GFAP+ (astrocytes) cells. Changes in the levels of astrocytes and microglia are associated with the activation of the NLRP3 inflammasome and increased levels of proinflammatory cytokines, such as IL1β and TNFα. Interestingly, microglia-specific ABCA7ko restored Aβ42 peptide levels and IBA1+ and GFAP+ and NLRP3-related gene expression to the original APPPS1 mouse levels. In primary glial cell cultures of APPPS1-hA7ko microglia and APPPS1 astrocytes from newborn pups, we observed that conditioned media from LPS-stimulated microglia was able to induce NLRP3 inflammasome expression and proinflammatory cytokine release in astrocytes.

Conclusions: Our data suggest that ABCA7 transporters regulate the communication between microglia and astrocytes through the NLRP3 inflammasome and the release of proinflammatory cytokines. This regulation implicates ABCA7 as a key driver ultimately involved in the persistence of the inflammatory response observed in AD.

ABC转运体A7通过NLRP3炎性体调节阿尔茨海默病小鼠的神经炎症。
背景:atp结合盒转运体A7位点(ABCA7)的特定遗传变异与阿尔茨海默病(AD)的风险增加有关。ABCA7在细胞膜上转运脂质,调节β肽的加工和清除,调节小胶质细胞和t细胞的功能,以维持大脑中的免疫稳态。在阿尔茨海默病的发病过程中,神经炎症是关键机制之一。因此,我们想通过NLRP3炎性体研究ABCA7在小胶质细胞活化中的具体作用。方法:建立人源化、可诱导ABCA7flx敲入小鼠模型,与APPPS1-21 β-淀粉样变性模型杂交,生成ABCA7ko和小胶质细胞cx3cr1特异性条件ABCA7ko AD小鼠。采用组织学、生化、分子和质谱等方法分析ABCA7的作用。结果:APPPS1小鼠组成性敲除Abca7基因后,Aβ42水平升高,IBA1+(小胶质细胞)和GFAP+(星形胶质细胞)细胞数量增加。星形胶质细胞和小胶质细胞水平的变化与NLRP3炎性小体的激活和促炎细胞因子(如il - 1β和tnf - α)水平的升高有关。有趣的是,小胶质细胞特异性ABCA7ko将Aβ42肽水平以及IBA1+、GFAP+和nlrp3相关基因表达恢复到小鼠原始APPPS1水平。在新生幼崽APPPS1- ha7ko小胶质细胞和APPPS1星形胶质细胞的原代胶质细胞培养中,我们观察到lps刺激的小胶质细胞条件培养基能够诱导星形胶质细胞NLRP3炎性小体表达和促炎细胞因子释放。结论:我们的数据表明ABCA7转运体通过NLRP3炎性体调节小胶质细胞和星形胶质细胞之间的通讯和促炎细胞因子的释放。这一调控暗示ABCA7是AD中观察到的炎症反应持续的关键驱动因素。
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来源期刊
Alzheimer's Research & Therapy
Alzheimer's Research & Therapy 医学-神经病学
CiteScore
13.10
自引率
3.30%
发文量
172
审稿时长
>12 weeks
期刊介绍: Alzheimer's Research & Therapy is an international peer-reviewed journal that focuses on translational research into Alzheimer's disease and other neurodegenerative diseases. It publishes open-access basic research, clinical trials, drug discovery and development studies, and epidemiologic studies. The journal also includes reviews, viewpoints, commentaries, debates, and reports. All articles published in Alzheimer's Research & Therapy are included in several reputable databases such as CAS, Current contents, DOAJ, Embase, Journal Citation Reports/Science Edition, MEDLINE, PubMed, PubMed Central, Science Citation Index Expanded (Web of Science) and Scopus.
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