Generation of Neural Progenitor Cells Overexpressing Alzheimer’s Disease Genes with Familial Mutations and Analysis of Pathological Changes of Alzheimer’s Cells in Vivo

We seek to evaluate the impact of candidate AD drugs on Abeta and tau pathology in human cellular AD models. In collaboration with Dr. Tanzi’s laboratory (Massachusetts General Hospital), we will test the impact of select candidate AD drugs on both Abeta and tau pathology in the 30 human neural cell culture models developed in Aim 4. In the first year, we found that SGSM41i, a candidate AD drug designed to specifically decrease the toxic Abeta42 generation, decreases not only the Abeta plaques but also the tau pathology in the 30 human cellular AD models. In the second year, we will test additional anti-Abeta drugs, including SGSM36, SGSM46 and SGSM49, which showed the higher potency in decreasing toxic Abeta species in vitro. We will test additional candidate AD drugs designed to block Abeta or Abeta-induced neuronal toxicity in the 30 human neural cell culture models. The overarching goal of this aim is to set up a unified platform that can be used for both studying the pathogenic mechanism of AD and evaluating target-based candidate AD drugs before human clinical trials.