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. 2018 Jul 25;10(1):69.
doi: 10.1186/s13195-018-0400-0.

Human fibroblast and stem cell resource from the Dominantly Inherited Alzheimer Network

Celeste M Karch  1 , Damián Hernández  2   3 , Jen-Chyong Wang  4 , Jacob Marsh  5 , Alex W Hewitt  2   3   6 , Simon Hsu  5 , Joanne Norton  5 , Denise Levitch  7 , Tamara Donahue  7 , Wendy Sigurdson  7 , Bernardino Ghetti  8 , Martin Farlow  9 , Jasmeer Chhatwal  10 , Sarah Berman  11 , Carlos Cruchaga  5 , John C Morris  7 , Randall J Bateman  7 ; Dominantly Inherited Alzheimer Network (DIAN); Alice Pébay  2   3 , Alison M Goate  12
Affiliations

Human fibroblast and stem cell resource from the Dominantly Inherited Alzheimer Network

Celeste M Karch et al. Alzheimers Res Ther. .

Abstract

Background: Mutations in amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) cause autosomal dominant forms of Alzheimer disease (ADAD). More than 280 pathogenic mutations have been reported in APP, PSEN1, and PSEN2. However, understanding of the basic biological mechanisms that drive the disease are limited. The Dominantly Inherited Alzheimer Network (DIAN) is an international observational study of APP, PSEN1, and PSEN2 mutation carriers with the goal of determining the sequence of changes in presymptomatic mutation carriers who are destined to develop Alzheimer disease.

Results: We generated a library of 98 dermal fibroblast lines from 42 ADAD families enrolled in DIAN. We have reprogrammed a subset of the DIAN fibroblast lines into patient-specific induced pluripotent stem cell (iPSC) lines. These cells were thoroughly characterized for pluripotency markers.

Conclusions: This library represents a comprehensive resource that can be used for disease modeling and the development of novel therapeutics.

Keywords: Amyloid precursor protein; Dominantly Inherited Alzheimer Network; Fibroblasts; Induced pluripotent stem cells; Presenilin 1; Presenilin 2.

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Conflict of interest statement

Ethics approval and consent to participate

The Washington University IRB reviewed the study protocol (IRB no. 201104178, 201306108). All subjects included in this study, or their proxies, gave written informed consent.

Consent for publication

Not applicable.

Competing interests

AMG is a member of the scientific advisory board for Denali Therapeutics and serves on the Genetic Scientific Advisory Panel for Pfizer. RJB receives laboratory research funding from the National Institutes of Health, Alzheimer’s Association, BrightFocus Foundation, Rainwater Foundation Tau Consortium, Association for Frontotemporal Degeneration, the Cure Alzheimer’s Fund, and the Tau SILK Consortium (AbbVie, Biogen, and Eli Lilly and Co.). Funding for clinical trials not related to this research include the National Institutes of Health, Alzheimer’s Association, Eli Lilly and Co., Hoffman-La Roche, Janssen, Avid Radiopharmaceuticals, GHR Foundation, and an anonymous foundation. RJB also receives research funding from the DIAN Pharma Consortium (AbbVie, Amgen, AstraZeneca, Biogen, Eisai, Eli Lilly and Co., Hoffman-La Roche, Janssen, Pfizer, and Sanofi). RJB has received honoraria from Janssen and Pfizer as a speaker and from Merck and Pfizer as an advisory board member. Washington University, RJB, and DH have equity ownership interests in C2N Diagnostics and receive royalty income based on technology (stable isotope labeling kinetics and blood plasma assay) licensed by Washington University to C2N Diagnostics. RJB receives income from C2N Diagnostics for serving on its scientific advisory board. Washington University, with RJB as coinventor, has submitted the U.S. nonprovisional patent application “Methods for Measuring the Metabolism of CNS Derived Biomolecules In Vivo” and a provisional patent application, “Plasma Based Methods for Detecting CNS Amyloid Deposition.” The remaining authors declare that they have no competing interests.

Publisher’s Note

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Figures

Fig. 1
Fig. 1
APP, PSEN1, and PSEN2 mutations. Schematic of the location of APP, PSEN1, and PSEN2 mutations reported in this collection. Green = variants of unknown pathogenicity. Aβ β-Amyloid
Fig. 2
Fig. 2
Dominantly Inherited Alzheimer Network (DIAN) fibroblast bank. a Representative bright-field image of human dermal fibroblasts. b–d Pie charts representing the percentage of APP, PSEN1, and PSEN2 mutations represented in the DIAN fibroblast bank (b), DIAN observational study (c), and reported in the Alzheimer’s disease (AD)/frontotemporal dementia (FTD) mutation database (d) [7]
Fig. 3
Fig. 3
Characterization of Dominantly Inherited Alzheimer Network (DIAN) induced pluripotent stem cell (iPSC) lines. Representative images of non-mutation carrier (left panel) and mutation carrier (right panel) iPSCs. a Immunostaining for pluripotency markers NANOG, SSEA4, OCT-3/4, and SOX2. b qPCR for pluripotency markers. c Karyotyping
See this image and copyright information in PMC

References

    1. Holtzman DM, Morris JC, Goate AM. Alzheimer’s disease: the challenge of the second century. Sci Transl Med. 2011;3:77sr71. - PMC - PubMed
    1. Guerreiro RJ, Gustafson DR, Hardy J. The genetic architecture of Alzheimer’s disease: beyond APP, PSENs and APOE. Neurobiol Aging. 2012;33:437–456. doi: 10.1016/j.neurobiolaging.2010.03.025. - DOI - PMC - PubMed
    1. Thinakaran G, Koo EH. Amyloid precursor protein trafficking, processing, and function. J Biol Chem. 2008;283:29615–29619. doi: 10.1074/jbc.R800019200. - DOI - PMC - PubMed
    1. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 2002;297:353–356. doi: 10.1126/science.1072994. - DOI - PubMed
    1. Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, Marcus DS, Cairns NJ, Xie X, Blazey TM, et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med. 2012;367:795–804. doi: 10.1056/NEJMoa1202753. - DOI - PMC - PubMed

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