Contribution of SORL1 in human iPSC-derived neurons and astrocytes to Alzheimer’s disease pathogenesis

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with heterogeneous etiology as suggested by genetic, neuropathological, and clinical evidence. Induced pluripotent stem cell (iPSC) technology can serve as a useful model system to study AD by providing an experimentally controlled system to analyze living human neurons and glia. By utilizing gene editing technology and generating iPSCs from individuals with diverse genetic backgrounds, we established a system to probe for molecular mechanisms underlying this heterogeneous disease. SORL1 is known as a neuronal sorting receptor, and it has been strongly implicated in the pathogenesis of AD through human genetic studies. To interrogate the potential role of SORL1 in human brain cells, we used CRISPR/Cas9 to generate SORL1 null iPSC lines followed by differentiation to neuron, astrocyte, microglia, and endothelial cell fates. Loss of SORL1 led to the greatest transcriptional profile change in neurons and astrocytes. In neurons, loss of SORL1 resulted in an elevation in Aβ and phospho-tau levels, and a reduction in APOE and CLU levels. Analyses of human iPSCs derived from a large cohort and single nucleus RNAseq of human postmortem brain further validated a neuron-specific relationship between APOE levels with SORL1. In astrocytes, loss of SORL1 resulted in elevated levels of cytokine secretion and enrichment of inflammation related pathways. Overall, we demonstrate that iPSCs can be a powerful system for identifying molecular pathways underlying AD and that SORL1 has a cell-type-specific role in neurons and astrocytes that could be relevant for AD pathogenesis.