CDiP technology for reverse engineering of sporadic Alzheimer’s disease

1. Kamboh MI. Genomics and Functional Genomics of Alzheimer’s Disease. Neurotherapeutics. 2021. https://doi.org/10.1007/S13311-021-01152-0

2. Guzman-Martinez L, Maccioni RB, Farías GA, Fuentes P, Navarrete LP. Biomarkers

for Alzheimer´s disease. Curr Alzheimer Res. 2019;16:518–28.

3. Naj AC, Schellenberg GD, Alzheimer’s Disease Genetics Consortium (ADGC).

Genomic variants, genes, and pathways of Alzheimer’s disease: An overview. Am

J Med Genet Part B Neuropsychiatr Genet. 2017;174:5–26.

4. Giau V, Van Bagyinszky E, Yang YS, Youn YC, An SSA, Kim SY. Genetic analyses of

early-onset Alzheimer’s disease using next generation sequencing. Sci Rep.

2019;9.

5. Takahashi K, Yamanaka S. Induction of Pluripotent Stem Cells from Mouse

Embryonic and Adult Fibroblast Cultures by Defined Factors. Cell. 2006;126:663–

76.

6. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction

of pluripotent stem cells from adult human fibroblasts by defined factors. Cell.

2007;131:861–72.

7. Shi Y, Inoue H, Wu JC, Yamanaka S. Induced pluripotent stem cell technology: a

decade of progress. Nat Rev Drug Discov. 2016;16:115–30.

8. Rubin LL. Stem cells and drug discovery: the beginning of a new era? Cell.

2008;132:549–52.

9. Zeng H, Guo M, Zhou T, Tan L, Chong CN, Zhang T, et al. An Isogenic Human ESC

Platform for Functional Evaluation of Genome-wide-Association-Study-Identified

Diabetes Genes and Drug Discovery. Cell Stem Cell. 2016;19:326–40.

10. Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, et al.

Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet. 2013;45:1452–8.

11. Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, et al. Genetic

meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and

implicates Aβ, tau, immunity and lipid processing. Nat Genet. 2019;51:414–30.

12. Mathys H, Davila-Velderrain J, Peng Z, Gao F, Mohammadi S, Young JZ, et al.

Single-cell transcriptomic analysis of Alzheimer’s disease. Nature. 2019;570:332–7.

13. De Strooper B, Karran E. The Cellular Phase of Alzheimer’s Disease. Cell.

2016;164:603–15.

14. Xia W. γ-Secretase and its modulators: twenty years and beyond. Neurosci Lett.

2019;701:162–9.

15. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and

problems on the road to therapeutics. Science. 2002;297:353–6.

16. Perrin RJ, Fagan AM, Holtzman DM. Multimodal techniques for diagnosis and

prognosis of Alzheimer’s disease. Nature. 2009;461:916–22.

17. Israel MA, Yuan SH, Bardy C, Reyna SM, Mu Y, Herrera C, et al. Probing sporadic

and familial Alzheimer’s disease using induced pluripotent stem cells. Nature.

2012;482:216–20.

18. Kondo T, Asai M, Tsukita K, Kutoku Y, Ohsawa Y, Sunada Y, et al. Modeling

Alzheimer’s disease with iPSCs reveals stress phenotypes associated with intracellular Aβ and differential drug responsiveness. Cell Stem Cell. 2013;12:487–96.

Journal of Human Genetics (2023) 68:231 – 235

T. Kondo et al.

235

19. Yagi T, Ito D, Okada Y, Akamatsu W, Nihei Y, Yoshizaki T, et al. Modeling familial

Alzheimer’s disease with induced pluripotent stem cells. Hum Mol Genet. 2011;

20:4530–9.

20. Chang, CY, Chen, SM, Lu, HE, Lai, SM, Lai, PS, Shen, PW, et al. N-butylidenephthalide attenuates Alzheimer’s disease-like cytopathy in Down syndrome

induced pluripotent stem cell-derived neurons. Sci Rep. 2015;5.

21. Oksanen M, Petersen AJ, Naumenko N, Puttonen K, Lehtonen Š, Gubert Olivé M,

et al. PSEN1 Mutant iPSC-Derived Model Reveals Severe Astrocyte Pathology in

Alzheimer’s Disease. Stem Cell Rep. 2017;9:1885–97.

22. Lehtonen Š, Höytyläinen I, Voutilainen J, Sonninen TM, Kuusisto J, Laakso M, et al.

Generation of a human induced pluripotent stem cell line from a patient with a

rare A673T variant in amyloid precursor protein gene that reduces the risk for

Alzheimer’s disease. Stem Cell Res. 2018;30:96–9.

23. Kondo T, Imamura K, Funayama M, Tsukita K, Miyake M, Ohta A, et al. iPSC-Based

Compound Screening and In Vitro Trials Identify a Synergistic Anti-amyloid β

Combination for Alzheimer’s Disease. Cell Rep. 2017;21:2304–12.

24. Young JE, Fong LK, Frankowski H, Petsko GA, Small SA, Goldstein LSB. Stabilizing

the Retromer Complex in a Human Stem Cell Model of Alzheimer’s Disease

Reduces TAU Phosphorylation Independently of Amyloid Precursor Protein. Stem

Cell Rep. 2018;10:1046–58.

25. Kimura J, Shimizu K, Kajima K, Yokosuka A, Mimaki Y, Oku N, et al. Nobiletin

Reduces Intracellular and Extracellular β-Amyloid in iPS Cell-Derived Alzheimer’s

Disease Model Neurons. Biol Pharm Bull. 2018;41:451–7.

26. Brownjohn PW, Smith J, Portelius E, Serneels L, Kvartsberg H, De Strooper B, et al.

Phenotypic Screening Identifies Modulators of Amyloid Precursor Protein Processing in Human Stem Cell Models of Alzheimer’s Disease. Stem Cell Rep.

2017;8:870–82.

27. Wang C, Najm R, Xu Q, Jeong D, Walker D, Balestra ME, et al. Gain of toxic

apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a

small-molecule structure corrector. Nat Med. 2018;24:647–57.

28. Kondo, T, Banno, H, Okunomiya, T, Amino, Y, Endo, K, Nakakura, A, et al.

Repurposing bromocriptine for Aβ metabolism in Alzheimer’s disease (REBRAnD)

study: randomised placebo-controlled double-blind comparative trial and openlabel extension trial to investigate the safety and efficacy of bromocriptine in

Alzheimer’s disease with presenilin 1 (PSEN1) mutations. BMJ Open 2021;11.

29. Huang Y-WA, Zhou B, Wernig M, Südhof TC. ApoE2, ApoE3, and ApoE4 Differentially Stimulate APP Transcription and Aβ Secretion. Cell. 2017;168:427–44. e21

30. Lin Y-T, Seo J, Gao F, Feldman HM, Wen H-L, Penney J, et al. APOE4 Causes

Widespread Molecular and Cellular Alterations Associated with Alzheimer’s

Disease Phenotypes in Human iPSC-Derived Brain Cell Types. Neuron. 2018;

98:1141–54.

31. Schmid, B, Prehn, KR, Nimsanor, N, Garcia, BIA, Poulsen, U, Jørring, I, et al. Generation of a set of isogenic, gene-edited iPSC lines homozygous for all main APOE

variants and an APOE knock-out line. Stem Cell Res. 2019;34.

32. Huang YWA, Zhou B, Nabet AM, Wernig M, Südhof TC. Differential Signaling

Mediated by ApoE2, ApoE3, and ApoE4 in Human Neurons Parallels Alzheimer’s

Disease Risk. J Neurosci. 2019;39:7408–27.

33. Young JE, Boulanger-weill J, Edland SD, Goldstein LSB, Herrera C, Israel MA, et al.

Elucidating molecular phenotypes caused by the SORL1 Alzheimer’s disease

genetic risk factor using human induced pluripotent stem cells. Cell Stem Cell.

2015;16:373–85.

34. Blanchard JW, Victor MB, Tsai LH. Dissecting the complexities of

Alzheimer disease with in vitro models of the human brain. Nat Rev Neurol.

2022;18:25–39.

35. Escott-Price V, Sims R, Bannister C, Harold D, Vronskaya M, Majounie E, et al.

Common polygenic variation enhances risk prediction for Alzheimer’s disease.

Brain. 2015;138:3673–84.

36. Desikan RS, Fan CC, Wang Y, Schork AJ, Cabral HJ, Cupples LA, et al. Genetic

assessment of age-associated Alzheimer disease risk: development and validation

of a polygenic hazard score. PLOS Med. 2017;14:e1002258.

37. Kondo T, Hara N, Koyama S, Yada Y, Tsukita K, Nagahashi A, et al. Dissection of

the polygenic architecture of neuronal Aβ production using a large sample of

Journal of Human Genetics (2023) 68:231 – 235

38.

39.

40.

41.

individual iPSC lines derived from Alzheimer’s disease patients. Nat Aging.

2022;2:125–39.

Cahan P, Daley GQ. Origins and implications of pluripotent stem cell variability

and heterogeneity. Nat Rev Mol Cell Biol 2013;14:357–68.

Watanabe A, Yamada Y & Yamanaka S. Epigenetic regulation in pluripotent stem

cells: a key to breaking the epigenetic barrier. Philos Trans R Soc Lond B Biol Sci.

2013;368.

Simpson DJ, Olova NN, Chandra T. Cellular reprogramming and epigenetic

rejuvenation. Clin Epigenet. 2021;13:1–10. 2021 131

Horvath S. DNA methylation age of human tissues and cell types. Genome Biol.

2013;14:1–20.

ACKNOWLEDGEMENTS

We would like to express our sincere gratitude to Mikie Iijima, Tomomi Urai, Miho

Nagata, Makiko Yasui, and Junko Enomoto for their valuable administrative support.

AUTHOR CONTRIBUTIONS

HI conceived the project. TK, YY, T I, and HI designed the experiment.

FUNDING

This research was funded in part by a grant for Core Center for iPS Cell Research of

Research Center Network for Realization of Regenerative Medicine from AMED to HI,

iPS Cell Research Fund to HI, Uehara Memorial Foundation to HI, KAKENHI

(21H02807) to HI, KAKENHI (17K16121) and (20K16599) to TK, KAKENHI (18K18452)

to TK, YY, and HI, the invited Project at iACT, Kyoto University Hospital to HI, Suzuki

Memorial Foundation to HI, and AMED (JP20dk0207045) to TI.

COMPETING INTERESTS

The authors declare no competing interests.

ADDITIONAL INFORMATION

Correspondence and requests for materials should be addressed to Haruhisa Inoue.

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