Funds are requested for the purchase of a Zeiss LSM510 laser confocal microscope. There is a strong justification for a new confocal laser microscope to replace our existing largely outdated model that currently serves all of the NIH-funded researchers at our Institute. The new microscope will extend the capabilities of our imaging facility, while providing a much-needed and valuable research tool for the seven applicant investigators and their co-investigators, which form the major user group. Instrumentation comparable to that requested is not available near NKI. The analysis and interpretation of structural and cell biological data by the best technological means available, including laser confocal microscopy, is of critical importance to the continuation and enhancement of ongoing research programs, and to the evolution of these programs in new directions. Acquisition of the new instrument will enable scientists throughout our institute to explore a diversity of topics organized around the theme of basic and translational neuroscience of neurodegenerative and neuropsychiatric diseases. All of the NIH-funded programs referenced in the application have components that require and would be strengthened by confocal laser microscopy. These are summarized as follows: 1) AD-related proteins following therapeutic intervention in animal models; 2) Expression Profiling in Neurodegenerative Disorders; 3) Cystatin C in cerebral hemorrhage and in Alzheimer's disease (AD); 4) The endocytic pathway in AD and Down's Syndrome; 5) The endosomal-autophagic-lysosomal system in AD Pathogenesis; 6) The role of disrupted cholesterol metabolism in AD pathogenesis; and 7) Signal Transduction in Neuropsychiatric Disease. ? ? An enhancement of the Institute's imaging capabilities will allow all applicant investigators to pursue funded research programs with greater efficiency and depth, to expand existing programs in new directions and to develop new programs. ? ?