Project Summary We have established a human iPS-derived neuronal-glial cell model system that we are using to (1) study AβO-induced neuronal cell cycle reentry (CCR) as well as (2) screen for compounds that inhibit AβO-induced neuronal CCR. We now propose to adapt this cell-based model system to evaluate the effects on SARS-CoV-2 spike protein-ACE2 binding on neuronal “fitness”, responsiveness and intracellular signaling as well as use to screen for small molecule inhibitors that may used for the next generation SARS-CoV-2 therapeutics.