The LINGO-1 protein is strongly associated with Alzheimer’s disease and is a novel drug target. LINGO-1 is a transmembrane protein that negatively regulates neuronal survival and myelination. LINGO-1 inhibition increases survival of multiple neural types and improves spatial learning, memory, and cognitive abilities in multiple mouse models. Thus, we hypothesize that reducing LINGO-1 levels in Alzheimer’s disease patients will stop neural death across multiple brain regions and improve cognitive function. Here, we propose to develop multiple knock-in reagents to identify small-molecule compounds that can reduce LINGO-1 protein expression.

We have developed a technology called PQR to measure protein production of any gene over time in single cells in vivo. We will use our PQR technology to monitor LINGO-1 protein expression in single neurons over time. We will use CRISPR-Cas9 to genome edit our PQR construct into the LINGO-1 gene in human neurons and in mice for drug discovery.