Alzheimer's disease (AD) is an irreversible neurodegenerative disorder, whose progression is closely associated with oxidative stress. It has long been speculated that the reactive oxygen species (ROS) level in AD brains is much higher than that in healthy brains. However, evidence from living beings is rare. Studies suggest that a vicious cycle revolves around amyloid beta (A?) and Tau production/aggregation, microglia responses, inflammatory responses, and ROS production. In this cycle, ROS species play a central role. Many clinical trials indicate that drugs can effectively engage with A? and remove A? plaques, but none of the trials have shown clear benefits of improving cognition. Nonetheless, it is not clear whether the removal of A?s can lead to the changes of ROS levels in brains during the therapy. To answer these fundamental and critically important questions, in this application, we propose to use Near Infrared Fluorescence (NIRF) imaging to monitor ROS changes in living AD brains during disease progression and therapy in preclinical animal models. Inspired by the chemistry of glow sticks, we have designed a NIRF probe, termed CRANAD-61 for detecting ROS. In glow sticks, oxalate esters react with H2O2 to produce chemiluminescence. In CRANAD-61, an oxalate moiety was utilized to react with ROS and to consequentially produce wavelength shifting. Our in vitro data showed that CRANAD-61 was highly sensitive and rapidly responsive to various ROS. Upon reacting with ROS, its excitation and emission wavelengths significantly shifted, and this shifting could be harnessed for dual-wavelength imaging. We showed that, for the first time, age-related increases in ROS levels in AD brains could be monitored with our NIRF imaging method. In this application, we propose to further structurally optimize CRANAD-61 by extending excitation/emission to make them suitable for dual-wavelength imaging in the NIR window. We will then use the optimized probe to monitor the changes of ROS during the progression of AD in transgenic mice, and during therapy with an A? antibody. We will investigate whether A?-lowering treatment can lead to a decrease of ROS, and whether a combination of A?-reduction and anti-oxidant or anti-inflammation therapies should be considered for AD treatment. The answers from our studies will improve and guide the paradigm of AD therapy regimens.
The purpose of this application is to develop imaging agents for reactive oxygen species of Alzheimer's disease. The proposed studies will provide beneficial information for the drug development for Alzheimer's disease.
|Yang, Jian; Yang, Jing; Li, Yuyan et al. (2018) Near-infrared Fluorescence Ocular Imaging (NIRFOI) of Alzheimer's Disease. Mol Imaging Biol :|