Yagi et al. (2011) and Yahata et al. (2011), were the first to generate hiPSCs from human fibroblasts in 2011. Differentiation of hiPSCs into forebrain neurons was achieved as described previously by Chambers et al. (2009). In addition, NSCs were induced with Noggin and SB431542 for 17 days to obtain cells that stained positive for the neuroectodermal marker, Nestin (Yahata et al., 2011). The presenilin (PS) mutations in familial AD were proved not to affect neuronal differentiation, where the ability to generate neurons (~80% TUJ1-positive cells) was comparable between PS-iPSCs and control iPSCs (Yagi et al., 2011). Noteworthy, the differentiated cells expressed APP, β-secretase, and γ-secretase components, and were found to secrete Aβ into the conditioned media in addition to expressing a glutamatergic phenotype. Another important finding was that neurons differentiated from iPSCs of familial AD patients with PS1 and PS2 mutations exhibited increased production of Aβ-42, and tau protein was found hyper-phosphorylated thus further showing that the differentiated iPSCs truly recapitulate the pathogenesis of AD (Yagi et al., 2011).
