NEUROPATHOLOGY CORE 1. MAIN OBJECTIVES AND NEW DIRECTIONS The Experimental Neuropathology Laboratory (ENL) at the Neurosciences and Pathology Departments at UCSD is primarily focused at better understanding the mechanisms of synaptic pathology and at developing new experimental therapies for Alzheimer's Disease (AD), Parkinson's Disease (PD), HIV associated dementia (HAD), and other neurodegenerative conditions. This laboratory is headed by Dr. Eliezer Masliah, who has collaborated with a number of neuroscientists on the La Jolla Torrey Pines Mesa and elsewhere, but these facilities have not been previously available to all neuroscientists as a Core. Dr. Masliah will serve as Director of the proposed New Neuropathology Core, which will be located at UCSD. We propose, via this grant proposal and in the spirit of the NIH Blueprint mission, to make this facility into a Core and to therefore make it readily available to other neuroscientists in the region. This new Core will foster further collaborations and enhance research into neurodegenerative disorders in the San Diego area. In recent years, with establishment of more sophisticated animal models of neurological disorders and the considerable growth of the neurosciences groups interested in neurodegenerative diseases at UCSD, the Burnham Institute for Medical Research (BIMR), The Scripps Research Institute (TSRI), and The Salk Institute, an increased demand for core services focused at characterizing neuropathological alterations in human and animal models has developed. Furthermore, interest has grown not only from the fields of AD, PD and HAD, but also in stroke, trinucleotide repeat disorders (such as Huntington's disease), taupathies, prion diseases, amyotrophic lateral sclerosis (ALS), and multiple sclerosis, just to mention a few. This has created a considerable need for the formation of a consolidated and unified Core Neuropathology Facility that will provide support and help coordinate efforts to all of these different programs. In this context, the overall objective of the Neuropathology Core is to provide to investigators in the La Jolla Neurosciences community a set of technical and neurobiological resources that allows analysis of the degenerative processes associated with neurological conditions in human brains and animal models from a comprehensive and dynamic perspective. The Core will allow the acquisition and analysis of Neuropathology related data with standardized protocols. CORE RESOURCE OBJECTIVES 1) Provide an array of techniques including histopathology, immunocytochemistry, microinjection, confocal microscopy, stereology, electron microscopy, digital imaging and 3D reconstruction to facilitate quantitative analysis of neuronal injury that will facilitate studies of the pathogenesis of degenerative, inflammatory and demyelinating CNS disorders. 2) Provide technical assistance on state-of-the-art neuropathological approaches such as twophoton confocal microscopy and immuno-electron microscopy. 3) Provide scientific consultation on molecular pathogenesis and targets of neurological disorders. 4) Support preliminary studies in human tissues and animal models that utilize neuropathology data. 5) Provide mentorship for students and junior faculty in the theory and techniques of neurobiology and neuropathology. 6) Collaborate with the other Cores of the program to disseminate information on neuropathology related methods of analysis.