those from control, cognitively normal centenarians [16] and found an increased ratio of Aβ42/Aβ40. iPSC-differentiated human neurons have been used to demonstrate accumulation and aggregation of intraneuronal Tau after Tau oligomers were internalized [17]. Similarly, oligomeric Aβ is shown to play a pathological role in inducing endoplasmic reticulum (ER) stress in iPSC-differentiated neurons [18]. These iPSCs were derived from atypical early-onset, autosomal recessive familial AD patients carrying an E693Δ mutation of APP that produces mutant Aβ lacking residue Glu22. When iPSCs were generated from an APP-E693Δ mutant carrier and differentiated into human neurons, Aβ oligomers accumulated in the neurons and induced ER stress, which could be prevented by treatment with a BACE1 inhibitor or docosahexaenoic acid (DHA) [18]. Thus, the iPSC paradigm was used to pinpoint the mechanism of DHA efficacy in a sub-population of subjects whose neurons have high levels of oligomeric Aβ. The iPSC-derived human neurons provide a screening tool for oligomer Aβ quantification and predict whether DHA or BACE1 inhibitors will alter the biology of disease in these AD patients. Such applications demonstrate the feasibility of using iPSC in targeted AD drug discovery and evaluation.
