The primary goals in the Goldstein lab are to unravel how molecular motors interact with, and control the behavior of, axonal vesicles, and to relate this understanding to the molecular basis of neuronal defects in Alzheimer's Disease (AD) and Niemann Pick type C disease.
We are taking advantage of pluripotent stem cell lines that contain known mutations that cause hereditary Alzheimer's disease, as well as Niemann Pick Type C disease. This latter disease is of interest because it directly ties cholesterol trafficking and transport to what appears to be a pediatric form of Alzheimer type dementia.
We are also using these cell lines and animal models to probe basic mechanisms of vesicle movement and sorting in neurons, and how such mechanisms inter-relate with disease development. In a related endeavor, we are probing how genetic variation predisposes to different neuronal phenotypes and disease by developing pluripotent stem cell lines carrying genomes of people who developed sporadic Alzheimer's disease or in one case carry susceptibility elements (from Craig Venter whose diploid genome is completely sequenced and which is known to harbor Alzheimer susceptibility variants).
To study these problems, we have collaborated with BD biosciences to develop new quantitative methods for generating and purifying neurons made from human embryonic stem cells and induced pluripotent stem cells. We have also developed quantitative methods for evaluating AD phenotypes in these cells.