title: Effect of potent γ-secretase modulator in human neurons derived from multiple presenilin 1-induced pluripotent stem cell mutant carriers.
abstract: OBJECTIVE
  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 γ-secretase inhibitor and γ-secretase modulator (GSM) in neurons derived from both normal control and 3 PS1 mutations (A246E, H163R, and M146L).
  
  
  METHODS
  Adult human skin biopsies were obtained from volunteers at the Alzheimer Disease Research Center, University of California, San Diego. Cell cultures were treated with γ-secretase inhibitor or GSM. Comparisons of total β-amyloid (Aβ) and Aβ peptides 38, 40, and 42 in the media were made between vehicle- vs drug-treated cultures.
  
  
  METHODS
  Soluble Aβ levels in the media were measured by enzyme-linked immunosorbent assay.
  
  
  RESULTS
  As predicted, mutant PS1 neurons exhibited an elevated Aβ42:Aβ40 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 Aβ42, Aβ40, and Aβ38 and in the Aβ42:Aβ40 ratio, with no change in the total Aβ levels.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla.
authors.forename: Qing
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla.
authors.forename: Shannon
authors.initials: S
authors.lastname: Waltz
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla.
authors.forename: Grace
authors.initials: G
authors.lastname: Woodruff
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla3Capitalbio, San Diego, California.
authors.forename: Joe
authors.initials: J
authors.lastname: Ouyang
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla4Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas.
authors.forename: Mason A
authors.initials: MA
authors.lastname: Israel
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Herrera
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla.
authors.forename: Floyd
authors.initials: F
authors.lastname: Sarsoza
authors.affiliation: Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Charlestown.
authors.forename: Rudolph E
authors.initials: RE
authors.lastname: Tanzi
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla.
authors.forename: Edward H
authors.initials: EH
authors.lastname: Koo
authors.affiliation: Mary S Easton Center for Alzheimer's Disease Research, Department of Neurology, University of California, Los Angeles.
authors.forename: John M
authors.initials: JM
authors.lastname: Ringman
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla.
authors.forename: Lawrence S B
authors.initials: LS
authors.lastname: Goldstein
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Wagner
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla.
authors.forename: Shauna H
authors.initials: SH
authors.lastname: Yuan
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000187:drug effects / Q000378:metabolism*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001381:Azepines / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000201:enzymology / Q000378:metabolism*; D010446:Peptide Fragments / Q000187:drug effects / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics*
chemical_list: D016229:Amyloid beta-Peptides; D000893:Anti-Inflammatory Agents; D001381:Azepines; D015415:Biomarkers; C484278:N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D000409:Alanine