Aβ43 is the earliest depositing Aβ species in APP transgenic mouse brain and is converted to Aβ41 by two active domains of ACE.
Aβ43 is the earliest depositing Aβ species in APP transgenic mouse brain and is converted to Aβ41 by two active domains of ACE.
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Aβ43是APP转基因小鼠大脑中最早沉积的Aβ种类，并通过ACE的两个活性结构域转化为Aβ41。
DOI：
10.1016/j.ajpath.2013.01.053
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发表时间：
2013
期刊：
影响因子：
6
通讯作者：
Komano H
中科院分区：
文献类型：
--
作者：
Zou K;Liu J;Watanabe A;Hiraga S;Liu S;Tanabe C;Maeda T;Terayama Y;Takahashi S;Michikawa M;Komano H
淀粉样蛋白-β蛋白(A-β)在其羧基末端长度不等。较长的Aβ物种，Aβ43和Aβ42，是高度淀粉样变性的，在阿尔茨海默病(AD)患者的大脑中比Aβ40更频繁地沉积。然而，Aβ43在脑内沉积的特征以及Aβ43与Aβ42或Aβ40之间的关系尚不清楚。我们提供的证据表明，在突变的淀粉样前体蛋白转基因小鼠的脑中，Aβ43的沉积出现得早于Aβ42和Aβ40的沉积，表明Aβ43是最早的沉积物种。此外，我们还发现AD患者血清中Aβ43水平和Aβ43/Aβ42比值升高，提示它们可作为AD的诊断血液标志物。我们进一步证明，血管紧张素转换酶可将Aβ43转化为Aβ41。值得注意的是，这种Aβ43到Aβ41的转换活动需要ACE的两个活性结构域。抑制血管紧张素转换酶活性可显著增加Aβ43在APPTG小鼠脑组织中的沉积。我们的结果表明，Aβ43是脑实质中最早沉积的物种，Aβ43可能触发较晚的Aβ42和Aβ40沉积，或可能转化为Aβ42和Aβ40斑块。这两个ACE域的活性可能对降低血清中Aβ43水平和减少脑Aβ43沉积具有重要意义。
Amyloid-β protein (Aβ) varies in length at its carboxyl terminus. The longer Aβ species, Aβ43and Aβ42, are highly amyloidogenic and deposit more frequently than Aβ40in the brain of Alzheimer disease (AD) patients. However, the characterization of Aβ43deposition in the brain and the relationship between Aβ43and Aβ42or Aβ40remain unclear. We provide evidence that Aβ43deposition appears earlier than Aβ42and Aβ40deposition in the brain of mutant amyloid precursor protein transgenic (APPtg) mice, suggesting that Aβ43is the earliest-depositing species. In addition, we found increased Aβ43levels and Aβ43/Aβ42ratios in the serum of AD patients, suggesting their use as diagnostic blood biomarkers for AD. We further show that angiotensin-converting enzyme (ACE) converts Aβ43to Aβ41. Notably, this Aβ43-to-Aβ41converting activity requires two active domains of ACE. Inhibition of ACE activity significantly enhanced Aβ43deposition in APPtg mouse brain. Our results suggest that Aβ43is the earliest-depositing species in brain parenchyma and that Aβ43may trigger later Aβ42and Aβ40deposition or may be converted to Aβ42and Aβ40plaques. Activities of both ACE domains may be important for reducing Aβ43levels in serum and reducing brain Aβ43deposition.