Developing human cellular models to understand biological mechanisms linked to AD genetic risk

Abstract

Mechanisms underlying late-onset sporadic Alzheimer's disease are genetically and biologically diverse. There is an outstanding need to identify modifiable cellular pathways associated with loci that increase AD risk. Furthermore, these pathways likely function differently in the diverse cell types of the CNS. Human induced pluripotent stem cells (hiPSCs) are an attractive model to address these challenges. hiPSCs can be differentiated to multiple cell types in two and three-dimensional formats. Using living human cells, novel cellular phenotypes can be uncovered and employed in therapeutic screens.We have applied this methodology to understand the role of the AD risk gene, SORL1 in endo-lysosomal trafficking in human neurons and microglia. SORL1 is a well-established AD risk gene and functions as an endosomal sorting receptor, known for regulating APP processing. Our data suggests multiple roles for SORL1 in endolysosomal trafficking beyond regulating amyloid beta peptide levels in neurons. We generated hiPSC lines with SORL1 AD-associated variants as well as loss of SORL1 function.In neurons and microglia derived from hiPSCs, we document changes in endosome morphology, sequestration of neurotrophin and synaptic receptors in early and recycling endosomes, impairments in phagocytosis and mis-trafficking of substrates to lysosomes. We also demonstrate that treatment with small molecules that enhance endosomal trafficking are able to ameliorate some of these phenotypes.Collectively are data shows that distinct cellular phenotypes can be modeled by manipulation of an AD risk genes and that strategies enhancing endosomal trafficking should be considered as therapeutic targets for AD.