Project Summary Alzheimer's disease (AD) is an irreversible neurodegenerative disease with its underlying cause poorly understood. Although many research have been conducted to understand its pathological origin using advanced imaging technologies, current discoveries have mainly stemmed from studies on microscopic systems with limited number of cells. While increasingly many evidences have indicated that the interaction among various groups of cells across the entire nervous system holds the key to those unanswered questions in AD, largescale volumetric investigation are limited by current imaging technologies. First, microscale methods used in conventional histopathology, such as electron or light microscopy, require extensive tissue sectioning for thick samples, leading to prolonged imaging time and the difficulty of 3D reconstruction from 2D images due to tissue deformation. On the other end, insufficient spatial resolution and limited molecular specificity of macroscale approaches, such as MR/PET /CT, have made them less attractive for pathological studies. Thus, the goal of this project is to develop an optical imaging method that not only provides high resolution and molecular contrast suitable for the pathology of the nervous systems in AD mouse models, but also offers enabling high-throughput for those large-scale investigations demanded by many of today's AD research. This proposal plans to address the above imaging needs by creating coherent optical imaging apparatus to provide the enabling high-throughput and high resolution, by developing new tissue processing methods to offer the molecular contrast in intact tissues, by building computational tools to assist the biological interpretation of imaging results. The outcome of the proposed research is expected to be a set of new research tools that facilitate large-cohort studies on AD mouse models with brain-wide big-data acquisition and analysis. This mentored project is aimed to facilitate the Pl (Dr. Jian Ren) to achieve his goal of obtaining research independence. Through the proposed research, the Pl will obtain complementary expertise from his mentors, a team of leading scientists including Dr. Brett Bouma (optical imaging), Dr. Bradley Hyman (neurology and AD), Dr. Sangeeta Bhatia (nanomedicine and tissue engineering), Dr. Tayyaba Hasan (photodynamic therapy), Dr. Edward Boyden (neuroscience and optogenetics), and Dr. Bruce Fischl (computational neuroimaging and MRI). This combined technical strength will be integrated with training on career development skill, facilitating the transition of the Pl to an independent investigator in the biomedical field. The Pl will conduct this project mainly in the Wellman Center for Photomedicine at Massachusetts General Hospital, which is surrounded by several world-renowned universities and research institutions in both life and physical sciences. Leveraging the support from the Pl's mentors, he will have access to numerous research facilitie...