Human‐Derived Induced Pluripotent Stem Cells‐Based Disease Models of the Alzheimer’s Disease (AD) Patients Expressed AD Phenotypes and Responded to 17β‐Estradiol Treatment

Abstract Background Neuronal models of both familial and sporadic cases of Alzheimer’s Disease (fAD/sAD) were generated from the human‐derived induced pluripotent stem cells (iPSCs) of AD patients. Using this in vitro cellular models, AD‐like phenotypes was analyzed with or without 17β‐estradiol, the sex hormone that are supposed to be involved in the AD pathogenesis. Method 5 lines of iPSCs comprised of 1 healthy control, 2 fAD, 2 sAD were differentiated to neurons with a newly established neuronal differentiation method. The AD‐like phenotypes such as secreted Aβ peptides and neuronal excitability were measured by ELISA and Ca‐imaging (Fluo‐8 indicator). In addition, the neuronal complexity and excitability were examined after long (4 days) and short (15 minutes) 17β‐estradiol treatment, respectively. Result The neurons were successfully induced from the iPSCs with the newly established differentiation method. The neurons induced from AD lines secreted more Aβ(1‐40) and Aβ(1‐42) peptides and increased Ca oscillations compared to the control line. The treatment with 17β‐estradiol to neurons promoted the neuronal complexity and cellular excitability. Conclusion Neurons derived from the iPSCs of the AD patients expressed AD phenotypes and responded to the treatment of 17β‐estradiol. Thus, this suggested the therapeutic effects of sex steroid hormones to AD can be evaluated in human cells. This enables us to examine the variability of estradiol response among patients and plan clinical trials based on the responsiveness.