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Reporting amyloid beta levels via bioluminescence imaging with amyloid reservoirs inAlzheimer's disease models

By Jing Yang, Weihua Ding, Biyue Zhu, Sherri Zhen, Shi Kuang, Can Martin Zhang, Peng Wang, Fan Yang, Liuyue Yang, Wei Yin, Rudolph Tanzi, Shiqian Shen, Chongzhao Ran

Posted 07 Jun 2021
bioRxiv DOI: 10.1101/2021.06.05.447217

Bioluminescence imaging has changed daily practice in preclinical research of cancers and other diseases in the last decades; however, it has been rarely applied in preclinical research of Alzheimer's disease (AD). In this report, we demonstrated that bioluminescence imaging could be used to report the levels of amyloid beta (Abeta). Bioluminescence imaging has changed daily practice in preclinical research of cancers and other diseases in the last decades; however, it has been rarely applied in preclinical research of Alzheimer's disease (AD). In this report, we demonstrated that bioluminescence imaging could be used to report the levels of amyloid beta (Abeta) species in vivo. We hypothesized that AkaLumine, a newly discovered substrate for luciferase, could bind to Abeta aggregates and plaques. We further speculated that the Abeta species have the reservoir capacity to sequester and release AkaLumine to control the bioluminescence intensity, which could be used to report the levels of Abetas. 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 aka Luciferase (AkaLuc), a new luciferase that generates bioluminescence in the near infrared window. As expected, compared to the control group, we observed that the Abeta group showed lower bioluminescence intensity due to AkaLumine sequestering at early time points, while higher intensity due to AkaLumine releasing at later time points. Lastly, we demonstrated that this method could be used to monitor AD progression and 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 Abeta 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 daily practice of preclinical AD research.

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