Amyloid beta (A?) plaques constitute one of the most distinctive morphological hallmarks of Alzheimer?s disease (AD). In the past decades, the contribution of A? plaques to the overall cognitive decline in AD has been debated extensively. Postmortem studies suggest that plaque abundance does not correlate strongly with severity of sporadic AD. Conversely, preclinical studies provide strong evidence that plaques are clear sites of pathology and are associated with the presence of dystrophic neurites and the loss of dendritic spines in their surroundings. Furthermore, additional evidence suggests that plaques may impair mitochondrial function and calcium homeostasis, which lead to rapid neuron cell death. Recent evidence indicates that A? plaques transform in a dynamic way. As they develop, the plaques have a different impact on the environment in which they reside. Data shows that at the early stage of growth, A? plaques lead to higher toxicity than in the later/mature stage. Based on recent experimental findings, we hypothesize that plaques of high toxicity are ?active? plaques, while plaques of low (or no) toxicity are ?silent? plaques, and the abundance of ?active plaques? has better correlations with the severity of AD than the number of total plaques. However, methods for differentiating active and silent plaques are currently lacking. During the formation and growth of the plaques, numerous reactive oxygen species (ROS) species are generated, and a vicious cycle ensues involving active plaques and ROS. Moreover, microglia that surround the active plaques also release ROS. Therefore, we tentatively define active plaques as deposits that are closely associated with high concentration of ROS and surrounded with increased numbers of microglia. We hypothesize that the local concentrations of ROS can be used to identify active plaques. Although evidence shows that active plaques exist throughout the course of AD progression, techniques and specific imaging probes to distinguish these active plaques have not been actively developed yet. In this application, we propose to design fluorescent probes to detect the active ?malignant? plaques. We believe that our technology will significantly contribute to understanding the fundamental pathology of AD and will potentially assist the development of efficient treatments for AD, particularly at earlier stages before the onset of clinically-observable cognitive deficits.
The purpose of this application is to establish a method to image active and toxic amyloid beta plaques in brain of Alzheimer's disease. The proposed studies will be beneficial for future treatment of Alzheimer's disease.
