Johnson, Noah Ray PHD

We have discovered that apolipoprotein E (apoE) promotes Alzheimer's disease by binding to the amyloid-beta peptide (Aβ) and converting into a toxic species that kills neurons and causes neurodegeneration, with the apoE4 form being the most effective catalyst of Aβ. To help inform future clinical trials, we have carried out a high- throughput screen and identified a set of small molecule drugs that prevent apoE4 from promoting the formation of Aβ oligomers and fibrils that lead to Alzheimer's disease. Here, we propose to further evaluate our most promising apoE-Aβ inhibitors for their ability to prevent the pathological functions of apoE4 in human induced pluripotent stem cell (iPSC)-derived cerebral organoid models of Down syndrome, and we will also evaluate their ability to improve cognition and shift Alzheimer's disease-associated biomarker profiles towards normal in Dp16 Down syndrome mice that express human APOE4.