Directed Conversion of Alzheimer's Disease Patient Skin Fibroblasts into Functional Neurons

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2011 Aug 6

PMID 21816272

Citations 130

Authors

Liang Qiang

Ryousuke Fujita

Toru Yamashita

Sergio Angulo

Herve Rhinn

David Rhee

Claudia Doege

Lily Chau

Laetitia Aubry

William B Vanti

Herman Moreno

Asa Abeliovich

Affiliations

Soon will be listed here.

Abstract

Directed conversion of mature human cells, as from fibroblasts to neurons, is of potential clinical utility for neurological disease modeling as well as cell therapeutics. Here, we describe the efficient generation of human-induced neuronal (hiN) cells from adult skin fibroblasts of unaffected individuals and Alzheimer's patients, using virally transduced transcription regulators and extrinsic support factors. hiN cells from unaffected individuals display morphological, electrophysiological, and gene expression profiles that typify glutamatergic forebrain neurons and are competent to integrate functionally into the rodent CNS. hiN cells from familial Alzheimer disease (FAD) patients with presenilin-1 or -2 mutations exhibit altered processing and localization of amyloid precursor protein (APP) and increased production of Aβ, relative to the source patient fibroblasts or hiN cells from unaffected individuals. Together, our findings demonstrate directed conversion of human fibroblasts to a neuronal phenotype and reveal cell type-selective pathology in hiN cells derived from FAD patients.

Citing Articles

Exploring the Skin Brain Link: Biomarkers in the Skin with Implications for Aging Research and Alzheimer's Disease Diagnostics.

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References

Shen J, Kelleher 3rd R . The presenilin hypothesis of Alzheimer's disease: evidence for a loss-of-function pathogenic mechanism. Proc Natl Acad Sci U S A. 2007; 104(2):403-9. PMC: 1766397. DOI: 10.1073/pnas.0608332104. View

Rhinn H, Marchand-Leroux C, Croci N, Plotkine M, Scherman D, Escriou V . Housekeeping while brain's storming Validation of normalizing factors for gene expression studies in a murine model of traumatic brain injury. BMC Mol Biol. 2008; 9:62. PMC: 2500043. DOI: 10.1186/1471-2199-9-62. View

Repetto E, Yoon I, Zheng H, Kang D . Presenilin 1 regulates epidermal growth factor receptor turnover and signaling in the endosomal-lysosomal pathway. J Biol Chem. 2007; 282(43):31504-16. DOI: 10.1074/jbc.M704273200. View

Hardy J, Selkoe D . The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002; 297(5580):353-6. DOI: 10.1126/science.1072994. View

De Strooper B, Annaert W . Novel research horizons for presenilins and γ-secretases in cell biology and disease. Annu Rev Cell Dev Biol. 2010; 26:235-60. DOI: 10.1146/annurev-cellbio-100109-104117. View

Abeliovich A, Doege C . Reprogramming therapeutics: iPS cell prospects for neurodegenerative disease. Neuron. 2009; 61(3):337-9. PMC: 3659427. DOI: 10.1016/j.neuron.2009.01.024. View

Walker E, Martinez M, Brunkan A, Goate A . Presenilin 2 familial Alzheimer's disease mutations result in partial loss of function and dramatic changes in Abeta 42/40 ratios. J Neurochem. 2005; 92(2):294-301. DOI: 10.1111/j.1471-4159.2004.02858.x. View

Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K . Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007; 131(5):861-72. DOI: 10.1016/j.cell.2007.11.019. View

Bentahir M, Nyabi O, Verhamme J, Tolia A, Horre K, Wiltfang J . Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms. J Neurochem. 2006; 96(3):732-42. DOI: 10.1111/j.1471-4159.2005.03578.x. View

10.

Cataldo A, Barnett J, Pieroni C, Nixon R . Increased neuronal endocytosis and protease delivery to early endosomes in sporadic Alzheimer's disease: neuropathologic evidence for a mechanism of increased beta-amyloidogenesis. J Neurosci. 1997; 17(16):6142-51. PMC: 6568334. View

11.

Takahashi K, Yamanaka S . Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006; 126(4):663-76. DOI: 10.1016/j.cell.2006.07.024. View

12.

Vassar R, Bennett B, Kahn S, Mendiaz E, Denis P, Teplow D . Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science. 1999; 286(5440):735-41. DOI: 10.1126/science.286.5440.735. View

13.

Thinakaran G, Harris C, Ratovitski T, Davenport F, Slunt H, Price D . Evidence that levels of presenilins (PS1 and PS2) are coordinately regulated by competition for limiting cellular factors. J Biol Chem. 1997; 272(45):28415-22. DOI: 10.1074/jbc.272.45.28415. View

14.

Macleod D, Dowman J, Hammond R, Leete T, Inoue K, Abeliovich A . The familial Parkinsonism gene LRRK2 regulates neurite process morphology. Neuron. 2006; 52(4):587-93. DOI: 10.1016/j.neuron.2006.10.008. View

15.

Davis R, Weintraub H, Lassar A . Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell. 1987; 51(6):987-1000. DOI: 10.1016/0092-8674(87)90585-x. View

16.

Forti L, Pouzat C, Llano I . Action potential-evoked Ca2+ signals and calcium channels in axons of developing rat cerebellar interneurones. J Physiol. 2000; 527 Pt 1:33-48. PMC: 2270052. DOI: 10.1111/j.1469-7793.2000.00033.x. View

17.

Nixon R, Cataldo A . Lysosomal system pathways: genes to neurodegeneration in Alzheimer's disease. J Alzheimers Dis. 2006; 9(3 Suppl):277-89. DOI: 10.3233/jad-2006-9s331. View

18.

Muzumdar M, Tasic B, Miyamichi K, Li L, Luo L . A global double-fluorescent Cre reporter mouse. Genesis. 2007; 45(9):593-605. DOI: 10.1002/dvg.20335. View

19.

Llano I, Bezanilla F . Current recorded from a cut-open giant axon under voltage clamp. Proc Natl Acad Sci U S A. 1980; 77(12):7484-6. PMC: 350529. DOI: 10.1073/pnas.77.12.7484. View

20.

Cataldo A, Hamilton D, Barnett J, Paskevich P, Nixon R . Properties of the endosomal-lysosomal system in the human central nervous system: disturbances mark most neurons in populations at risk to degenerate in Alzheimer's disease. J Neurosci. 1996; 16(1):186-99. PMC: 6578706. View