Access the full text.
Sign up today, get DeepDyve free for 14 days.
V. Coric, C. Dyck, S. Salloway, N. Andreasen, M. Brody, R. Richter, H. Soininen, S. Thein, T. Shiovitz, G. Pilcher, Susan Colby, L. Rollin, R. Dockens, C. Pachai, E. Portelius, U. Andreasson, K. Blennow, H. Soares, C. Albright, H. Feldman, R. Berman (2012)
Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease.Archives of neurology, 69 11
L. Serneels, J. Biervliet, K. Craessaerts, T. Dejaegere, Katrien Horré, Tine Houtvin, H. Esselmann, S. Paul, M. Schäfer, O. Berezovska, B. Hyman, B. Sprangers, R. Sciot, L. Moons, M. Jucker, Zhixiang Yang, P. May, E. Karran, J. Wiltfang, R. D'Hooge, B. Strooper (2009)
γ-Secretase Heterogeneity in the Aph1 Subunit: Relevance for Alzheimer’s DiseaseScience, 324
Benedikt Kretner, Akio Fukumori, Amelie Gutsmiedl, Richard Page, T. Luebbers, G. Galley, K. Baumann, C. Haass, H. Steiner (2011)
Attenuated Aβ42 Responses to Low Potency γ-Secretase Modulators Can Be Overcome for Many Pathogenic Presenilin Mutants by Second-generation Compounds*The Journal of Biological Chemistry, 286
Camryn Berk, M. Sabbagh (2013)
Successes and Failures for Drugs in Late-Stage Development for Alzheimer’s DiseaseDrugs & Aging, 30
Thorlákur Jónsson, J. Atwal, S. Steinberg, J. Snaedal, P. Jonsson, Sigurbjorn Bjornsson, H. Stefánsson, P. Sulem, D. Gudbjartsson, Janice Maloney, Kwame Hoyte, Amy Gustafson, Yichin Liu, Yanmei Lu, T. Bhangale, R. Graham, J. Huttenlocher, G. Bjornsdottir, O. Andreassen, E. Jönsson, A. Palotie, T. Behrens, O. Magnusson, A. Kong, U. Thorsteinsdóttir, R. Watts, K. Stefánsson (2012)
A mutation in APP protects against Alzheimer’s disease and age-related cognitive declineNature, 488
Stuart Chambers, Christopher Fasano, E. Papapetrou, M. Tomishima, M. Sadelain, L. Studer (2009)
Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signalingNature biotechnology, 27
Jun Peng, Qiuyue Liu, M. Rao, Xianmin Zeng (2013)
Using Human Pluripotent Stem Cell–Derived Dopaminergic Neurons to Evaluate Candidate Parkinson’s Disease Therapeutic Agents in MPP+ and Rotenone ModelsJournal of Biomolecular Screening, 18
Danwei Huangfu, R. Maehr, Wenjun Guo, A. Eijkelenboom, Melinda Snitow, Alice Chen, D. Melton (2008)
Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compoundsNature Biotechnology, 26
H. Kawasaki, K. Mizuseki, S. Nishikawa, S. Kaneko, Y. Kuwana, S. Nakanishi, S. Nishikawa, Y. Sasai (2000)
Induction of Midbrain Dopaminergic Neurons from ES Cells by Stromal Cell–Derived Inducing ActivityNeuron, 28
Ira Lott, Elizabeth Head (2001)
Down syndrome and Alzheimer's disease: a link between development and aging.Mental retardation and developmental disabilities research reviews, 7 3
E. Chan, Sutheera Ratanasirintrawoot, In-Hyun Park, Philip Manos, Y. Loh, Hongguang Huo, Justine Miller, O. Hartung, Junsung Rho, T. Ince, G. Daley, T. Schlaeger (2009)
Live cell imaging distinguishes bona fide human iPS cells from partially reprogrammed cellsNature Biotechnology, 27
M. Kounnas, A. Danks, Soan Cheng, C. Tyree, Elizabeth Ackerman, Xulun Zhang, Kwangwook Ahn, Phuong Nguyen, Dan Comer, Long-fei Mao, Chengzhi Yu, David Pleynet, P. Digregorio, G. Velicelebi, K. Stauderman, W. Comer, W. Mobley, Yue-Ming Li, S. Sisodia, R. Tanzi, S. Wagner (2010)
Modulation of γ-Secretase Reduces β-Amyloid Deposition in a Transgenic Mouse Model of Alzheimer's DiseaseNeuron, 67
Shauna Yuan, M. Shaner (2013)
Bioengineered stem cells in neural development and neurodegeneration researchAgeing Research Reviews, 12
Kazutoshi Takahashi, K. Tanabe, M. Ohnuki, Megumi Narita, T. Ichisaka, K. Tomoda, S. Yamanaka (2007)
Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined FactorsCell, 131
Shauna Yuan, J. Martin, J. Elia, Jessica Flippin, Rosanto Paramban, M. Hefferan, J. Vidal, Yangling Mu, Rhiannon Killian, Mason Israel, N. Emre, S. Marsala, M. Marsala, F. Gage, L. Goldstein, C. Carson (2011)
Cell-Surface Marker Signatures for the Isolation of Neural Stem Cells, Glia and Neurons Derived from Human Pluripotent Stem CellsPLoS ONE, 6
S. Wagner, C. Zhang, Soan Cheng, Phuong Nguyen, Xulun Zhang, Kevin Rynearson, Rong Wang, Yueming Li, S. Sisodia, W. Mobley, R. Tanzi (2014)
Soluble γ-Secretase Modulators Selectively Inhibit the Production of the 42-Amino Acid Amyloid β Peptide Variant and Augment the Production of Multiple Carboxy-Truncated Amyloid β SpeciesBiochemistry, 53
I. Kola, John Landis (2004)
Can the pharmaceutical industry reduce attrition rates?Nature Reviews Drug Discovery, 3
Gabsang Lee, Christina Ramirez, Hyesoo Kim, Nadja Zeltner, Becky Liu, C. Radu, B. Bhinder, Yong Kim, In Choi, Bipasha Mukherjee-Clavin, Hakim Djaballah, L. Studer (2012)
Identification of Compounds that Rescue IKBKAP Expression in Familial Dysautonomia-iPS CellsNature biotechnology, 30
Daniel Oehlrich, Didier Berthelot, H. Gijsen (2011)
γ-Secretase modulators as potential disease modifying anti-Alzheimer's drugs.Journal of medicinal chemistry, 54 3
M. Okochi, S. Tagami, K. Yanagida, Mako Takami, T. Kodama, Kohji Mori, T. Nakayama, Y. Ihara, M. Takeda (2013)
γ-secretase modulators and presenilin 1 mutants act differently on presenilin/γ-secretase function to cleave Aβ42 and Aβ43.Cell reports, 3 1
D. Holtzman, J. Morris, A. Goate (2011)
Alzheimer’s Disease: The Challenge of the Second CenturyScience Translational Medicine, 3
M. Grs̆ković, A. Javaherian, B. Strulovici, G. Daley (2011)
Induced pluripotent stem cells — opportunities for disease modelling and drug discoveryNature Reviews Drug Discovery, 10
L. Chávez-Gutiérrez, Leen Bammens, I. Benilova, A. Vandersteen, Manasi Benurwar, M. Borgers, Sam Lismont, Lujia Zhou, Simon Cleynenbreugel, H. Esselmann, J. Wiltfang, L. Serneels, E. Karran, H. Gijsen, J. Schymkowitz, F. Rousseau, K. Broersen, B. Strooper (2012)
The mechanism of γ-Secretase dysfunction in familial Alzheimer diseaseThe EMBO Journal, 31
MZ Kounnas, AM Danks, S Cheng (2010)
Modulation of gamma-secretase reduces beta-amyloid deposition in a transgenic mouse model of Alzheimer’s disease., 67
P. Koch, I. Tamboli, J. Mertens, Patrick Wunderlich, J. Ladewig, Kathrin Stüber, H. Esselmann, J. Wiltfang, O. Brüstle, J. Walter (2012)
Presenilin-1 L166P mutant human pluripotent stem cell-derived neurons exhibit partial loss of γ-secretase activity in endogenous amyloid-β generation.The American journal of pathology, 180 6
Y. Mitani, J. Yarimizu, K. Saita, H. Uchino, H. Akashiba, Y. Shitaka, K. Ni, N. Matsuoka (2012)
Differential Effects between γ-Secretase Inhibitors and Modulators on Cognitive Function in Amyloid Precursor Protein-Transgenic and Nontransgenic MiceThe Journal of Neuroscience, 32
S. Kumar-Singh, J. Theuns, Bianca Broeck, D. Pirici, K. Vennekens, E. Corsmit, M. Cruts, B. Dermaut, Rong Wang, C. Broeckhoven (2006)
Mean age‐of‐onset of familial alzheimer disease caused by presenilin mutations correlates with both increased Aβ42 and decreased Aβ40Human Mutation, 27
D. Scheuner, C. Eckman, C. Eckman, M. Jensen, X. Song, M. Citron, N. Suzuki, T. Bird, J. Hardy, M. Hutton, W. Kukull, Eric Larson, E. Levy-Lahad, M. Viitanen, E. Peskind, P. Poorkaj, G. Schellenberg, R. Tanzi, W. Wasco, L. Lannfelt, D. Selkoe, S. Younkin (1996)
Secreted amyloid β–protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's diseaseNature Medicine, 2
Christina Crump, Douglas Johnson, Yue-Ming Li (2013)
Development and mechanism of γ-secretase modulators for Alzheimer's disease.Biochemistry, 52 19
G Lee, CN Ramirez, H Kim (2012)
Large-scale screening using familial dysautonomia induced pluripotent stem cells identifies compounds that rescue IKBKAP expression., 30
Rachel Potter, B. Patterson, D. Elbert, Vitaliy Ovod, Tom Kasten, Wendy Sigurdson, K. Mawuenyega, Tyler Blazey, A. Goate, R. Chott, K. Yarasheski, D. Holtzman, J. Morris, T. Benzinger, R. Bateman (2013)
Increased in Vivo Amyloid-β42 Production, Exchange, and Loss in Presenilin Mutation CarriersScience Translational Medicine, 5
Mako Takami, Y. Nagashima, Y. Sano, Seiko Ishihara, M. Morishima-kawashima, S. Funamoto, Y. Ihara (2009)
γ-Secretase: Successive Tripeptide and Tetrapeptide Release from the Transmembrane Domain of β-Carboxyl Terminal FragmentThe Journal of Neuroscience, 29
Mason Israel, Shauna Yuan, C. Bardy, Sol Reyna, Yangling Mu, C. Herrera, M. Hefferan, S. Gorp, Kristopher Nazor, F. Boscolo, C. Carson, L. Laurent, M. Marsala, F. Gage, A. Remes, E. Koo, L. Goldstein (2012)
Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cellsNature, 482
ImportanceAlthough 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. ObjectiveTo 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). Design, Setting, and ParticipantsAdult 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. Main Outcomes and MeasuresSoluble Aβ levels in the media were measured by enzyme-linked immunosorbent assay. ResultsAs 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 and RelevanceThis 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.
JAMA Neurology – American Medical Association
Published: Dec 1, 2014
Read and print from thousands of top scholarly journals.
Already have an account? Log in
Bookmark this article. You can see your Bookmarks on your DeepDyve Library.
To save an article, log in first, or sign up for a DeepDyve account if you don’t already have one.
Copy and paste the desired citation format or use the link below to download a file formatted for EndNote
Access the full text.
Sign up today, get DeepDyve free for 14 days.
All DeepDyve websites use cookies to improve your online experience. They were placed on your computer when you launched this website. You can change your cookie settings through your browser.