Imaging asparaginyl endopeptidase (AEP) in the live brain as a biomarker for Alzheimer's disease.
Imaging asparaginyl endopeptidase (AEP) in the live brain as a biomarker for Alzheimer's disease.
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对活体大脑中的天冬酰胺酰内肽酶 (AEP) 进行成像，作为阿尔茨海默病的生物标志物
DOI：
10.1186/s12951-021-00988-0
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发表时间：
2021-08-19
影响因子：
10.2
通讯作者：
Song M
中科院分区：
文献类型：
--
作者：
Wang SS;Liu ZK;Liu JJ;Cheng Q;Wang YX;Liu Y;Ni WW;Chen HZ;Song M
早期生物标志物的发现是阿尔茨海默病（AD）诊断的长期追求目标。年龄是大多数AD的最大危险因素，越来越多的证据表明，大脑中天冬酰胺内肽酶（AEP）的年龄依赖性升高可能是预测AD的一个新的生物学标志物。然而，由于哺乳动物的AEP存在于许多器官中，且体液中AEP的水平与其在脑实质中的浓度不成正比，因此这种推测仍有待于适当的测定方法来探索。为此，我们将金纳米粒子（AuNPs）修饰成aep响应成像探针，并选择转基因APPswe/PS1dE9 （APP/PS1）小鼠作为AD动物模型。我们的目的是确定脑AEP成像是否可以用于预测AD病理。该aep响应成像探针AuNPs-Cy5.5-A&C由两个粒子组成，AuNPs-Cy5.5-AK和AuNPs-Cy5.5-CABT，分别用Ala-Ala-Asn-Cys-Lys （AK）和2-氰基-6-氨基苯并噻唑（CABT）修饰。我们发现AuNPs-Cy5.5-A&C可以被AEP选择性激活，聚集并发出强烈的荧光。此外，AuNPs-Cy5.5-A&C在各种细胞系中表现出普遍的适用性，其荧光强度与这些细胞中的AEP活性具有良好的相关性。在APP/PS1转基因小鼠的大脑中，AEP活性在AD的早期疾病阶段（老年斑形成和认知障碍之前）升高。δ-分泌酶抑制剂11 （10 mg kg−1,p.o）对AEP进行药理学抑制，可减少β-淀粉样蛋白（Aβ）的产生，改善记忆丧失。因此，AEP升高是AD发病的早期征兆。最后，我们发现使用这种AEP响应探针进行活体成像可以监测APP/PS1小鼠大脑中AEP的上调。目前的工作提供了一个概念证明，通过体内成像分析评估大脑AEP活动是早期诊断AD的潜在生物标志物。在线版本包含补充材料，可在10.1186/s12951-021-00988-0获得。
Discovery of early-stage biomarkers is a long-sought goal of Alzheimer’s disease (AD) diagnosis. Age is the greatest risk factor for most AD and accumulating evidence suggests that age-dependent elevation of asparaginyl endopeptidase (AEP) in the brain may represent a new biological marker for predicting AD. However, this speculation remains to be explored with an appropriate assay method because mammalian AEP exists in many organs and the level of AEP in body fluid isn’t proportional to its concentration in brain parenchyma. To this end, we here modified gold nanoparticle (AuNPs) into an AEP-responsive imaging probe and choose transgenic APPswe/PS1dE9 (APP/PS1) mice as an animal model of AD. Our aim is to determine whether imaging of brain AEP can be used to predict AD pathology. This AEP-responsive imaging probe AuNPs-Cy5.5-A&C consisted of two particles, AuNPs-Cy5.5-AK and AuNPs-Cy5.5-CABT, which were respectively modified with Ala–Ala–Asn–Cys–Lys (AK) and 2-cyano-6-aminobenzothiazole (CABT). We showed that AuNPs-Cy5.5-A&C could be selectively activated by AEP to aggregate and emit strong fluorescence. Moreover, AuNPs-Cy5.5-A&C displayed a general applicability in various cell lines and its florescence intensity correlated well with AEP activity in these cells. In the brain of APP/PS1 transgenic mice , AEP activity was increased at an early disease stage of AD that precedes formation of senile plaques and cognitive impairment. Pharmacological inhibition of AEP with δ-secretase inhibitor 11 (10 mg kg−1, p.o.) reduced production of β-amyloid (Aβ) and ameliorated memory loss. Therefore, elevation of AEP is an early sign of AD onset. Finally, we showed that live animal imaging with this AEP-responsive probe could monitor the up-regulated AEP in the brain of APP/PS1 mice. The current work provided a proof of concept that assessment of brain AEP activity by in vivo imaging assay is a potential biomarker for early diagnosis of AD. The online version contains supplementary material available at 10.1186/s12951-021-00988-0.
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影响因子：
3.9
作者：
Shukla, R;Bansal, V;Sastry, M
通讯作者：
Sastry, M
影响因子：
5.3
作者：
Bhowmick, Saurav;D'Mello, Veera;Abdul-Muneer, P. M.
通讯作者：
Abdul-Muneer, P. M.
影响因子：
15.1
作者：
Shin, Yoojin;Choi, Se Hoon;Tanzi, Rudolph E.
通讯作者：
Tanzi, Rudolph E.
影响因子：
3.2
作者：
Hong, Jong-Ah;Choi, Na-Eun;Lee, Jiyoun
通讯作者：
Lee, Jiyoun
DOI：
10.1186/s13195-020-00721-3
发表时间：
2020-11-19
期刊：
Alzheimer's research & therapy
影响因子：
--
作者：
Sörensen A;Blazhenets G;Schiller F;Meyer PT;Frings L;Alzheimer Disease Neuroimaging Initiative
通讯作者：
Alzheimer Disease Neuroimaging Initiative