Bioluminescence Imaging with Functional Amyloid Reservoirs in Alzheimer's Disease Models.
Bioluminescence Imaging with Functional Amyloid Reservoirs in Alzheimer's Disease Models.
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DOI：
10.1021/acs.analchem.3c02358
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发表时间：
2023-09
影响因子：
7.4
通讯作者：
Jing Yang;Weihua Ding;Biyue Zhu;Sherri Y. Zhen;Shi Kuang;Jun Yang;C. Zhang;Peng Wang;
中科院分区：
文献类型：
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作者：
Jing Yang;Weihua Ding;Biyue Zhu;Sherri Y. Zhen;Shi Kuang;Jun Yang;C. Zhang;Peng Wang;
在过去的几十年里，生物发光成像已经改变了癌症和其他疾病临床前研究的日常实践;然而，它很少应用于阿尔茨海默病（AD）的临床前研究。在这篇文章中，我们证明了生物发光成像可以用来报告体内β淀粉样蛋白（Aβ）的水平。我们假设AkaLumine，一种新发现的荧光素酶底物，可以与Aβ聚集体和斑块结合。我们进一步推测，Aβ聚集体/纤维/斑块可以被认为是“功能性淀粉样蛋白”，其具有隔离和释放AkaLumine的储存器功能，以控制生物发光强度，其可以用于报告Aβs的水平。我们的假设已经通过体外溶液测试，模拟研究与脑组织和小鼠，双光子成像与AD小鼠，并在体内生物发光成像使用转基因AD小鼠病毒转导AkaLuciferase（AkaLuc），一种新的荧光素酶，产生生物发光的近红外窗口。正如预期的那样，与对照组相比，我们观察到Aβ组由于AkaLumine在早期时间点的螯合而显示出较低的生物发光强度，而较高的强度是由于AkaLumine在较晚时间点的释放。最后，我们证明了这种方法可用于监测AD进展和avagacestat（一种研究充分的γ-分泌酶抑制剂）的治疗效果。重要的是，在体内生物发光信号和测试的AD小鼠的Aβ负荷之间建立了良好的相关性（R2 = 0.81）。我们相信，我们的方法可以很容易地实施到日常成像实验中，并有巨大的潜力改变临床前AD研究的日常实践。
Bioluminescence imaging has changed the daily practice of preclinical research on cancer and other diseases over the last few decades; however, it has rarely been applied in preclinical research on Alzheimer's disease (AD). In this Article, we demonstrated that bioluminescence imaging could be used to report the levels of amyloid beta (Aβ) species in vivo. We hypothesized that AkaLumine, a newly discovered substrate for luciferase, could bind to Aβ aggregates and plaques. We further speculated that the Aβ aggregates/fibrils/plaques could be considered as "functional amyloids", which have a reservoir function to sequester and release AkaLumine to control the bioluminescence intensity, which could be used to report the levels of Aβs. Our hypotheses have been validated via in vitro solution tests, mimic studies with brain tissues and mice, two-photon imaging with AD mice, and in vivo bioluminescence imaging using transgenic AD mice that were virally transduced with AkaLuciferase (AkaLuc), a new luciferase that generates bioluminescence in the near-infrared window. As expected, compared to the control group, we observed that the Aβ group showed lower bioluminescence intensity due to AkaLumine sequestering at early time points, while higher intensity was due to AkaLumine releasing at later time points. Lastly, we demonstrated that this method could be used to monitor AD progression and the therapeutic effectiveness of avagacestat, a well-studied gamma-secretase inhibitor. Importantly, a good correlation (R2 = 0.81) was established between in vivo bioluminescence signals and Aβ burdens of the tested AD mice. We believe that our approach can be easily implemented into daily imaging experiments and has tremendous potential to change the daily practice of preclinical AD research.