Mobley, William C MD

Because Down syndrome dramatically alters aspects of CNS development, the transformative challenge is to use and invent new approaches and technologies to identify which of the many brain cell types and maturation processes are affected by HSA21, and to reveal the mechanistic basis for the occurrence of AD in DS. We will use the powerful multiplexing of single cell (nuclei) in matched control and DS frontal cortical and hippocampal specimens, coupled with exploration of development of neurons and astrocytes in cortical organoid cultures derived from Down iPSCs, and to link the underlying age-related alterations in development and function of each cell type in the CNS applying a strategy to conditionally silence the HSA21 allele using an Xist-based strategy. Finally, we will use murine DS models to perform lineage trancing approaches to unlock the mechanisms by which the disordered neural cell types emerge in DS-AD.

An extra copy of the gene for APP is necessary for Alzheimer disease (AD) in Down syndrome (DS); the APP products responsible include the 99 residue C-terminal fragment (C99) and Aβ42. Increased C99 and Aβ42 are present in mouse models of DS and of AD. To reduce C99 and Aβ42, and prevent or lessen neurodegeneration, we will treat with the γ-secretase modulator (GSM) BPN15606, a small molecule that increases γ-secretase activity and that lessened neurodegeneration in preliminary studies.