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Induced pluripotent stem-cell-derived models of sporadic and familial Alzheimer's disease


Our understanding of Alzheimer's disease (AD) pathogenesis is currently limited by difficulties in obtaining live neurons from patients and the inability to model the sporadic form of AD. It may be possible to overcome these challenges by reprogramming primary cells from patients into induced pluripotent stem cells (iPSCs). We reprogrammed primary fibroblasts from patients with familial AD (caused by a duplication of APP, APPDp, sporadic AD (sAD), and non-demented control individuals (NDCs) into iPSC lines. Neurons from both APPDp patients and one sAD patient exhibited significantly higher levels of secreted Aß¹⁻⁴⁰, phospho-tauThr²³¹ and active GSK3ß, relative to control neurons. Treatment of APPDp neurons with ß-secretase inhibitors, but not [gamma]-secretase inhibitors, caused significant reductions in pTau and GSK3ß levels. These results suggest a direct relationship between APP proteolytic processing and tau phosphorylation in human neurons. Additionally, we observed that neurons with the genome of one sAD patient exhibited the phenotypes seen in familial AD samples. More generally, we demonstrate that iPSC technology can be used to observe phenotypes relevant to AD, even though it can take decades for overt disease to manifest in patients

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