Late-onset sporadic Alzheimer's disease modeling using patient-derived cells: A review
Late-onset sporadic Alzheimer's disease (LOAD) is the most common form of dementia. The disease is characterized by progressive loss of memory and behavioral changes followed by neurodegeneration of all cortical areas. While the contribution of genetic and environmental factors is important, advanced aging remains the most important disease risk factor. Because LOAD does not naturally occur in most know animal species, except humans, studies have traditionally relied on the use of transgenic mice modeling rare, early-onset genetic forms of Alzheimer's disease. Hence, the development of more representative LOAD models through reprograming of patient-derived cells into neuronal, glial, and immune cells became a necessity to better understand the disease origin and pathophysiology. Herein, and focusing on neurons, we review current work in the field and compare results obtained with two different reprograming methods to generate patient-derived neuronal cells: the induced pluripotent stem cell and induced neuron technologies. We also evaluate if these models can faithfully mimic cellular and molecular pathologies observed in LOAD patient's brains. Here, we show new ATAC-seq data that support that iPSC can faithfully model LOAD, with an increased number of peaks showing chromatin relaxation in LOAD neurons Overall design: iPSC reprogrammed from LOAD patient fibroblasts were differentiated into neurons for 60 days followed by an ATAC-seq