Effect of Potent γ-Secretase Modulator in Human Neurons Derived From Multiple Presenilin 1-Induced Pluripotent Stem Cell Mutant Carriers

IMPORTANCE Although considerable effort has been expended developing drug candidates for Alzheimer disease, none have yet succeeded owing to the lack of efficacy or to safety concerns. One potential shortcoming of current approaches to Alzheimer disease drug discovery and development is that they rely primarily on transformed cell lines and animal models that substantially overexpress wild-type or mutant proteins. It is possible that drug development failures thus far are caused in part by the limits of these approaches, which do not accurately reveal how drug candidates will behave in naive human neuronal cells. OBJECTIVE To analyze purified neurons derived from human induced pluripotent stem cells from patients carrying 3 different presenilin 1 (PS1) mutations and nondemented control individuals in the absence of any overexpression. We tested the efficacy of gamma-secretase inhibitor and gamma-secretase modulator (GSM) in neurons derived from both normal control and 3 PS1 mutations (A246E, H163R, and M146L). DESIGN, SETTING, AND PARTICIPANTS Adult human skin biopsieswere obtained from volunteers at the Alzheimer Disease Research Center, University of California, San Diego. Cell cultures were treated with.-secretase inhibitor or GSM. Comparisons of total beta-amyloid (A beta) and A beta peptides 38, 40, and 42 in the media were made between vehicle-vs drug-treated cultures. MAIN OUTCOMES AND MEASURES Soluble A beta levels in the media were measured by enzyme-linked immunosorbent assay. RESULTS As predicted, mutant PS1 neurons exhibited an elevated A beta 42: A beta 40 ratio (P < .05) at the basal state as compared with the nondemented control neurons. Treatment with a potent non-nonsteroidal anti-inflammatory druglike GSM revealed a new biomarker signature that differs from all previous cell types and animals tested. This new signature was the same in both the mutant and control neurons and consisted of a reduction in A beta 42, A beta 40, and A beta 38 and in the A beta 42: A beta 40 ratio, with no change in the total Ab levels. CONCLUSIONS AND RELEVANCE This biomarker discrepancy is likely due to overexpression of amyloid precursor protein in the transformed cellular models. Our results suggest that biomarker signatures obtained with such models are misleading and that human neurons derived from human induced pluripotent stem cells provide a unique signature that will more accurately reflect drug response in human patients and in cerebrospinal fluid biomarker changes observed during GSM treatment.