Person:

Moore, Anna

In brains of Alzheimer’s disease (AD), reactive oxygen species (ROS) levels are significantly higher than that of healthy brains. Evidence suggests that, during AD onset and progression, a vicious cycle revolves around amyloid beta (Aβ) production, aggregation, plaque formation, microglia/immunological responses, inflammation, and ROS production. In this cycle, ROS species play a central role, and H2O2 is one of the most important ROS species. In this report, we have designed a fluorescent imaging probe CRANAD-88, which is capable of cascade amplifying near infrared fluorescence (NIRF) signals at three levels upon interacting with H2O2 in AD brains. We demonstrated that the amplification was feasible in vitro and in vivo. Remarkably, we showed that, for the first time, it was feasible to monitor the changes of H2O2 concentrations in AD brains before and after treatment with an H2O2 scavenger. Our method opens new revenues to investigate H2O2 in AD brains and can be very instructive for drug development.

PET imaging is a widely applicable but a very expensive technology. On-site synthesis is one important contributor to the high cost. In this report, we demonstrated the feasibility of a synthesis-free method for PET imaging of brown adipose tissue (BAT) and translocator protein 18 kDa (TSPO) via a combination of disulfiram, an FDA approved drug for alcoholism, and 64CuCl2 (termed 64Cu-Dis). In this method, a step-wise injection protocol of 64CuCl2 and disulfiram was used to accomplish the purpose of synthesis-free. Specifically, disulfiram, an inactive 64Cu ligand, was first injected to allow it to metabolize into diethyldithiocarbamate (DDC), a strong 64Cu ligand, which can chelate 64CuCl2 from the following injection to form the actual PET tracer in situ. Our blocking studies, western blot, and tissue histological imaging suggested that the observed BAT contrast was due to 64Cu-Dis binding to TSPO, which was further confirmed as a specific biomarker for BAT imaging using [18F]-F-DPA, a TSPO-specific PET tracer. Our studies, for the first time, demonstrated that TSPO could serve as a potential imaging biomarker for BAT. We believe that our strategy could be extended to other targets while significantly reducing the cost of PET imaging.

The biological fate of amyloid beta (Aβ) species is a fundamental question in Alzheimer’s disease (AD) pathogenesis. The competition between clearance and aggregation of Aβs is critical for the onset of AD. Copper has been widely considered to be an inducer of harmful crosslinking of Aβs, and an important triggering factor for the onset of AD. In this report, however, we present data to show that copper can also be an inducer of Aβ degradation in the presence of a large excess of well-known intrinsic (such as dopamine) or extrinsic (such as vitamin C) anti-oxidants. The degraded fragments were identified using SDS-Page gels, and validated via nanoLC-MS/MS. A tentative mechanism for the degradation was proposed and validated with model peptides. In addition, we performed electrophysiological analysis to investigate the synaptic functions in brain slices, and found that in the presence of a significant excess of vitamin C, Cu(ii) could prevent an Aβ-induced deficit in synaptic transmission in the hippocampus. Collectively, our evidence strongly indicated that a proper combination of copper and anti-oxidants might have a positive effect on the prevention of AD. This double-edged function of copper in AD has been largely overlooked in the past. We believe that our report is very important for fully understanding the function of copper in AD pathology.