大脑中淀粉样蛋白-β的逐渐积累导致 APP 基因敲入小鼠肝脏和肾脏中蛋白质表达的改变

IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Journal of pharmaceutical sciences Pub Date : 2024-11-01 DOI:10.1016/j.xphs.2024.10.051
Shingo Ito, Yumi Iwata, Mitsumi Otsuka, Yui Kaneko, Seiryo Ogata, Ryotaro Yagi, Tatsuki Uemura, Takeshi Masuda, Takashi Saito, Takaomi Saido, Sumio Ohtsuki
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引用次数: 0

摘要

肝脏和肾脏功能受损会影响阿尔茨海默病(AD)的进展;然而,AD进展是否会影响这些重要器官的功能仍不清楚。在这里,我们利用定量蛋白质组学研究了以脑淀粉样蛋白-β(Aβ)积累为特征的阿尔茨海默病进展对 AppNL-G-F/NL-G-F (APP-KI) 小鼠肝肾功能的影响。基于SWATH的定量蛋白质组学发现,在Aβ积累的早期(2月龄)和中期(5月龄)阶段,小鼠肝脏和肾脏中的线粒体、药物代谢和药代动力学相关蛋白质发生了变化。值得注意的是,在5月龄APP-KI小鼠肝脏中,25种I/II期代谢酶(8种CYPs、7种UGTs、7种CESs和3种SLCs)和5种转运体(2种ABCs和3种SLCs)发生了显著变化;具体而言,Ugt1a9和Slc33a1蛋白丰度增加,而Ugt1a1和Abcc3蛋白丰度降低。在肾脏中,13 种 I/II 期代谢酶和 10 种 ABC-SLC 转运体发生了改变,包括 Ugt1a6、Ugt1a7、Slc22a7 和 Abcb1a。此外,白蛋白和α-1-酸性糖蛋白等对药物结合和分布至关重要的血浆蛋白也发生了改变。这些结果表明,大脑中Aβ的逐渐积累在改变肝脏和肾脏蛋白质丰度方面起着重要作用,可能会影响AD患者的药物代谢和处置。我们的研究结果为了解AD进展与器官功能障碍之间的复杂关系提供了新的视角。
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Progressive Amyloid-β Accumulation in the Brain leads to Altered Protein Expressions in the Liver and Kidneys of APP knock-in Mice.

Impaired hepatic and renal function influence Alzheimer's disease (AD) progression; however, whether AD progression affects these important organ functions remains unclear. Here, we investigated the impact of AD progression, characterized by brain amyloid-beta (Aβ) accumulation, on liver and kidney function of AppNL-G-F/NL-G-F (APP-KI) mice using quantitative proteomics. SWATH-based quantitative proteomics revealed changes in mitochondrial, drug metabolism, and pharmacokinetic-related proteins in mouse liver and kidneys during the early (2-month-old) and intermediate (5-month-old) stages of Aβ accumulation. Notably, in 5-month-old APP-KI mouse liver, 25 phase I/II metabolizing enzymes (8 CYPs, 7 UGTs, 7 CESs, and 3 SLCs) and five transporters (2 ABCs and 3 SLCs) were significantly altered; specifically, Ugt1a9 and Slc33a1 protein abundances increased, whereas Ugt1a1 and Abcc3 protein abundances decreased. In the kidneys, 13 phase I/II metabolizing enzymes and 10 ABC-SLC transporters were altered, including Ugt1a6, Ugt1a7, Slc22a7, and Abcb1a. Additionally, plasma proteins, such as albumin and alpha-1-acid glycoprotein, which are critical for drug binding and distribution, were also altered. These results underscore the significant role of progressive brain Aβ accumulation in modifying hepatic and renal protein abundances, potentially influencing drug metabolism and disposition in AD. Our findings provide novel insights into the complex relationship between AD progression and organ dysfunction.

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来源期刊
CiteScore
7.30
自引率
13.20%
发文量
367
审稿时长
33 days
期刊介绍: The Journal of Pharmaceutical Sciences will publish original research papers, original research notes, invited topical reviews (including Minireviews), and editorial commentary and news. The area of focus shall be concepts in basic pharmaceutical science and such topics as chemical processing of pharmaceuticals, including crystallization, lyophilization, chemical stability of drugs, pharmacokinetics, biopharmaceutics, pharmacodynamics, pro-drug developments, metabolic disposition of bioactive agents, dosage form design, protein-peptide chemistry and biotechnology specifically as these relate to pharmaceutical technology, and targeted drug delivery.
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