Modeling neurodegenerative disorders in adult somatic cells: A critical review
Received date: 10 Apr 2016
Accepted date: 12 Jun 2016
Published date: 05 Jul 2016
Copyright
Development of new therapeutic targets for neurodegenerative disorders has been hampered by a reliance on post mortem tissue that is representative of end-stage disease, or on animal models that fail to provide faithful analogs. However, rapid advances in cellular genetic reprogramming, in particular the induction of somatic cells into stem cells, or directly into neurons, has led to intense interest in modeling of human neurodegeneration in vitro. Here, we critically review current methods and recent progress in cellular models of Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Several challenges are identified, including technical variability, lack of degenerative phenotypes, neurodevelopmental age and establishing ground truths for models of sporadic disease. Recommendations for evaluating neurodegenerative cellular models are proposed along with suggestions for future research.
An Truong , Emily Si , Thomas Duncan , Michael Valenzuela . Modeling neurodegenerative disorders in adult somatic cells: A critical review[J]. Frontiers in Biology, 2016 , 11(3) : 232 -245 . DOI: 10.1007/s11515-016-1413-3
| 1 |
Anokye-Danso F, Snitow M, Morrisey E E (2012). How microRNAs facilitate reprogramming to pluripotency. J Cell Sci, 125(Pt 18): 4179–4187
|
| 2 |
Boulting G L, Kiskinis E, Croft G F, Amoroso M W, Oakley D H, Wainger B J, Williams D J, Kahler D J, Yamaki M, Davidow L, Rodolfa C T, Dimos J T, Mikkilineni S, MacDermott A B, Woolf C J, Henderson C E, Wichterle H, Eggan K (2011). A functionally characterized test set of human induced pluripotent stem cells. Nat Biotechnol, 29(3): 279–286
|
| 3 |
Braak H, Braak E 1998. Evolution of neuronal changes in the course of Alzheimer’s disease. In: Jellinger K, Fazekas F, Windisch M (eds.) Ageing and Dementia. Vienna: Springer Vienna
|
| 4 |
Braak H, Brettschneider J, Ludolph A C, Lee V M, Trojanowski J Q, Del Tredici K (2013). Amyotrophic lateral sclerosis—a model of corticofugal axonal spread. Nat Rev Neurol, 9(12): 708–714
|
| 5 |
Braak H, Ghebremedhin E, Rüb U, Bratzke H, Del Tredici K (2004). Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res, 318(1): 121–134
|
| 6 |
Brayne C (2007). The elephant in the room- healthy brains in later life, epidemiology and public health. Nat Rev Neurosci, 8(3): 233–239
|
| 7 |
Breitner J C (2015). Comment: Yet another “disconnect” between amyloid and Alzheimer disease? Neurology, 85(8): 698
|
| 8 |
Bruijn L I, Becher M W, Lee M K, Anderson K L, Jenkins N A, Copeland N G, Sisodia S S, Rothstein J D, Borchelt D R, Price D L, Cleveland D W (1997). ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron, 18(2): 327–338
|
| 9 |
Burkhardt M F, Martinez F J, Wright S, Ramos C, Volfson D, Mason M, Garnes J, Dang V, Lievers J, Shoukat-Mumtaz U, Martinez R, Gai H, Blake R, Vaisberg E, Grskovic M, Johnson C, Irion S, Bright J, Cooper B, Nguyen L, Griswold-Prenner I, Javaherian A (2013). A cellular model for sporadic ALS using patient-derived induced pluripotent stem cells. Mol Cell Neurosci, 56: 355–364
|
| 10 |
Byers B, Cord B, Nguyen H N, Schüle B, Fenno L, Lee P C, Deisseroth K, Langston J W, Pera R R, Palmer T D (2011). SNCA triplication Parkinson’s patient’s iPSC-derived DA neurons accumulate a-synuclein and are susceptible to oxidative stress. PLoS ONE, 6(11): e26159–e26159
|
| 11 |
Byrne J A (2008). Generation of isogenic pluripotent stem cells. Hum Mol Genet, 17(R1): R37–R41
|
| 12 |
Cairns N J,Perrin R J , Franklin E E, Carter D, Vincent B, Xie M, Bateman R J, Benzinger T, Friedrichsen K, Brooks W S, Halliday G M, McLean C, Ghetti B, Morris J C, the Alzheimer Disease Neuroimaging Initiative, the Dominantly Inherited Alzheimer Network (2015). Neuropathologic assessment of participants in two multi-center longitudinal observational studies: the Alzheimer Disease Neuroimaging Initiative (ADNI) and the Dominantly Inherited Alzheimer Network (DIAN). Neuropathology, 35(4): 390–400
|
| 13 |
Choi S H, Kim Y H, Hebisch M, Sliwinski C, Lee S, D’Avanzo C, Chen H, Hooli B, Asselin C, Muffat J, Klee J B, Zhang C, Wainger B J, Peitz M, Kovacs D M, Woolf C J, Wagner S L, Tanzi R E, Kim D Y (2014). A three-dimensional human neural cell culture model of Alzheimer’s disease. Nature, 515(7526): 274–278
|
| 14 |
Coan G, Mitchell C S (2015). An assessment of possible neuropathology and clinical relationships in 46 Sporadic amyotrophic lateral sclerosis patient autopsies. Neurodegener Dis, 15(5): 301–312
|
| 15 |
Collins P Y, Patel V, Joestl S S, March D, Insel T R, Daar A S, Anderson W, Dhansay M A, Phillips A, Shurin S, Walport M, Ewart W, Savill S J, Bordin I A, Costello E J, Durkin M, Fairburn C, Glass R I, Hall W, Huang Y, Hyman S E, Jamison K, Kaaya S, Kapur S, Kleinman A, Ogunniyi A, Otero-Ojeda A, Poo M M, Ravindranath V, Sahakian B J, Saxena S, Singer P A, Stein D J, the Scientific Advisory Board and the Executive Committee of the Grand Challenges on Global Mental Health (2011). Grand challenges in global mental health. Nature, 475(7354): 27–30
|
| 16 |
Crystal H A, Dickson D, Sliwinski M, Masur D, Blau A, Lipton R B (1996). Associations of status and change measures of neuropsychological function with pathologic changes in elderly, originally nondemented subjects. Arch Neurol, 53(1): 82–87
|
| 17 |
Dauer W, Przedborski S (2003). Parkinson’s disease: mechanisms and models. Neuron, 39(6): 889–909
|
| 18 |
Duan L, Bhattacharyya B J, Belmadani A, Pan L, Miller R J, Kessler J A (2014). Stem cell derived basal forebrain cholinergic neurons from Alzheimer’s disease patients are more susceptible to cell death. Mol Neurodegener, 9(1): 3–3
|
| 19 |
Fernández-Santiago R, Carballo-Carbajal I, Castellano G, Torrent R, Richaud Y, Sánchez-Danés A, Vilarrasa-Blasi R, Sánchez-Pla A, Mosquera J L, Soriano J, López-Barneo J, Canals J M, Alberch J, Raya Á, Vila M, Consiglio A, Martín-Subero J I, Ezquerra M, Tolosa E (2015). Aberrant epigenome in iPSC-derived dopaminergic neurons from Parkinson’s disease patients. EMBO Mol Med, 7(12): 1529–1546
|
| 20 |
Gandhi S, Wood N W (2010). Genome-wide association studies: the key to unlocking neurodegeneration? Nat Neurosci, 13(7): 789–794
|
| 21 |
Gurney M E, Pu H, Chiu A Y, Dal Canto M C, Polchow C Y, Alexander D D, Caliendo J, Hentati A, Kwon Y W, Deng H X, et (1994). Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science, 264(5166): 1772–1775
|
| 22 |
Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere M L, Pahwa J S, Moskvina V, Dowzell K, Williams A, Jones N, Thomas C, Stretton A, Morgan A R, Lovestone S, Powell J, Proitsi P, Lupton M K, Brayne C, Rubinsztein D C, Gill M, Lawlor B, Lynch A, Morgan K, Brown K S, Passmore P A, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith A D, Love S, Kehoe P G, Hardy J, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Schürmann B, Heun R, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frölich L, Hampel H, Hüll M, Rujescu D, Goate A M, Kauwe J S, Cruchaga C, Nowotny P, Morris J C, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn P P, Van Broeckhoven C, Livingston G, Bass N J, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw C E, Tsolaki M, Singleton A B, Guerreiro R, Mühleisen T W, Nöthen M M, Moebus S, Jöckel K H, Klopp N, Wichmann H E, Carrasquillo M M, Pankratz V S, Younkin S G, Holmans P A, O’Donovan M, Owen M J, Williams J (2009). Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet, 41(10): 1088–1093
|
| 23 |
Honda M, Minami I, Tooi N, Morone N, Nishioka H, Uemura K, Kinoshita A, Heuser J E, Nakatsuji N, Aiba K (2016). The modeling of Alzheimer’s disease by the overexpression of mutant Presenilin 1 in human embryonic stem cells. Biochem Biophys Res Commun, 469(3): 587–592
|
| 24 |
Hossini A M, Megges M, Prigione A, Lichtner B, Toliat M R, Wruck W, Schröter F, Nuernberg P, Kroll H, Makrantonaki E, Zouboulis C C, Adjaye J (2015). Induced pluripotent stem cell-derived neuronal cells from a sporadic Alzheimer’s disease donor as a model for investigating AD-associated gene regulatory networks. BMC Genomics, 16(1): 84
|
| 25 |
Hou P, Li Y, Zhang X, Liu C, Guan J, Li H, Zhao T, Ye J, Yang W, Liu K, Ge J, Xu J, Zhang Q, Zhao Y, Deng H (2013). Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science, 341(6146): 651–654
|
| 26 |
Hu W, Qiu B, Guan W, Wang Q, Wang M, Li W, Gao L, Shen L, Huang Y, Xie G, Zhao H, Jin Y, Tang B, Yu Y, Zhao J, Pei G (2015a). Direct conversion of normal and Alzheimer’s disease human fibroblasts into neuronal cells by small molecules. Cell Stem Cell, 17(2): 204–212
|
| 27 |
Hu Z, Pu J, Jiang H, Zhong P, Qiu J, Li F, Wang X, Zhang B, Yan Z, Feng J (2015b). Generation of naivetropic induced pluripotent stem cells from Parkinson’s disease patients for high-efficiency genetic manipulation and disease modeling. Stem Cells Dev, 24(21): 2591–2604
|
| 28 |
Israel M A, Yuan S H, Bardy C, Reyna S M, Mu Y, Herrera C, Hefferan M P, Van Gorp S, Nazor K L, Boscolo F S, Carson C T, Laurent L C, Marsala M, Gage F H, Remes A M, Koo E H, Goldstein L S B (2012). Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature, 482(7384): 216–220
|
| 29 |
Ittner L M, Götz J (2011). Amyloid-b and tau—a toxic pas de deux in Alzheimer’s disease. Nat Rev Neurosci, 12(2): 65–72
|
| 30 |
Kim D, Kim C H, Moon J I, Chung Y G, Chang M Y, Han B S, Ko S, Yang E, Cha K Y, Lanza R, Kim K S (2009). Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell, 4(6): 472–476
|
| 31 |
Kim Y H, Choi S H, D’Avanzo C, Hebisch M, Sliwinski C, Bylykbashi E, Washicosky K J, Klee J B, Brüstle O, Tanzi R E, Kim D Y (2015). A 3D human neural cell culture system for modeling Alzheimer’s disease. Nat Protoc, 10(7): 985–1006
|
| 32 |
Kondo T, Asai M, Tsukita K, Kutoku Y, Ohsawa Y, Sunada Y, Imamura K, Egawa N, Yahata N, Okita K, Takahashi K, Asaka I, Aoi T, Watanabe A, Watanabe K, Kadoya C, Nakano R, Watanabe D, Maruyama K, Hori O, Hibino S, Choshi T, Nakahata T, Hioki H, Kaneko T, Naitoh M, Yoshikawa K, Yamawaki S, Suzuki S, Hata R, Ueno S, Seki T, Kobayashi K, Toda T, Murakami K, Irie K, Klein W L, Mori H, Asada T, Takahashi R, Iwata N, Yamanaka S, Inoue H (2013). Modeling Alzheimer’s disease with iPSCs reveals stress phenotypes associated with intracellular Ab and differential drug responsiveness. Cell Stem Cell, 12(4): 487–496
|
| 33 |
Kyttälä A, Moraghebi R, Valensisi C, Kettunen J, Andrus C, Pasumarthy K K, Nakanishi M, Nishimura K, Ohtaka M, Weltner J, Van Handel B, Parkkonen O, Sinisalo J, Jalanko A, Hawkins R D, Woods N B, Otonkoski T, Trokovic R (2016). Genetic variability overrides the impact of parental cell type and determines iPSC differentiation potential. Stem Cell Rep, 6(2): 200–212
|
| 34 |
Ladewig J, Mertens J, Kesavan J, Doerr J, Poppe D, Glaue F, Herms S, Wernet P, Kögler G, Müller F J, Koch P, Brüstle O (2012). Small molecules enable highly efficient neuronal conversion of human fibroblasts. Nat Methods, 9(6): 575–578
|
| 35 |
Lambert J C,Heath S , Even G, Campion D, Sleegers K, Hiltunen M, Combarros O, Zelenika D, Bullido M J, Tavernier B, Letenneur L, Bettens K, Berr C, Pasquier F, Fiévet N, Barberger-Gateau P,Engelborghs S , De Deyn P, Mateo I, Franck A, Helisalmi S, Porcellini E, Hanon O, de Pancorbo M M, Lendon C, Dufouil C, Jaillard C, Leveillard T, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossù P, Piccardi P, Annoni G, Seripa D, Galimberti D, Hannequin D, Licastro F, Soininen H, Ritchie K, Blanché H, Dartigues J F, Tzourio C, Gut I, Van Broeckhoven C, Alpérovitch A, Lathrop M, Amouyel P, the European Alzheimer’s Disease Initiative Investigators (2009). Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet, 41(10): 1094–1099
|
| 36 |
Lancaster M A, Knoblich J A (2014). Generation of cerebral organoids from human pluripotent stem cells. Nat Protoc, 9(10): 2329–2340
|
| 37 |
Lancaster M A, Renner M, Martin C A, Wenzel D, Bicknell L S, Hurles M E, Homfray T, Penninger J M, Jackson A P, Knoblich J A (2013). Cerebral organoids model human brain development and microcephaly. Nature, 501(7467): 373–379
|
| 38 |
Lapasset L, Milhavet O, Prieur A, Besnard E, Babled A, Aït-Hamou N, Leschik J, Pellestor F, Ramirez J M, De Vos J, Lehmann S, Lemaitre J M (2011). Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state. Genes Dev, 25(21): 2248–2253
|
| 39 |
Lau S, Rylander Ottosson D, Jakobsson J, Parmar M (2014). Direct neural conversion from human fibroblasts using self-regulating and nonintegrating viral vectors. Cell Reports, 9(5): 1673–1680
|
| 40 |
Li W, Zhou H, Abujarour R, Zhu S, Young Joo J, Lin T, Hao E, Schöler H R, Hayek A, Ding S (2009). Generation of human-induced pluripotent stem cells in the absence of exogenous Sox2. Stem Cells, 27(12): 2992–3000
|
| 41 |
Lim S M, Choi W J, Oh K W, Xue Y, Choi J Y, Kim S H, Nahm M, Kim Y E, Lee J, Noh M Y, Lee S, Hwang S, Ki C S, Fu X D, Kim S H (2016). Directly converted patient-specific induced neurons mirror the neuropathology of FUS with disrupted nuclear localization in amyotrophic lateral sclerosis. Mol Neurodegener, 11(1): 8
|
| 42 |
Lin T, Ambasudhan R, Yuan X, Li W, Hilcove S, Abujarour R, Lin X, Hahm H S, Hao E, Hayek A, Ding S (2009). A chemical platform for improved induction of human iPSCs. Nat Methods, 6(11): 805–808
|
| 43 |
Liras A, Segovia C, Gabán A S (eds.) (2013). Induced Pluripotent Stem Cells: Therapeutic Applications in Monogenic and Metabolic Diseases, and Regulatory and Bioethical Considerations. InTechOpen
|
| 44 |
Liu M L, Zang T, Zhang C L (2016). Direct lineage reprogramming reveals disease-specific phenotypes of motor neurons from human ALS patients. Cell Reports, 14(1): 115–128
|
| 45 |
Liu M L, Zang T, Zou Y, Chang J C, Gibson J R, Huber K M, Zhang C L (2013). Small molecules enable neurogenin 2 to efficiently convert human fibroblasts into cholinergic neurons. Nat Commun, 4: 2183
|
| 46 |
Mahmoudi S, Brunet A (2012). Aging and reprogramming: a two-way street. Curr Opin Cell Biol, 24(6): 744–756
|
| 47 |
Marion R M, Strati K, Li H, Tejera A, Schoeftner S, Ortega S, Serrano M, Blasco M A (2009). Telomeres acquire embryonic stem cell characteristics in induced pluripotent stem cells. Cell Stem Cell, 4(2): 141–154
|
| 48 |
Mascalchi M, Salvi F, Valzania F, Marcacci G, Bartolozzi C, Tassinari C A (1995). Corticospinal tract degeneration in motor neuron disease. AJNR Am J Neuroradiol, 16(4 Suppl): 878–880
|
| 49 |
Mertens J, Paquola A C, Ku M, Hatch E, Böhnke L, Ladjevardi S, McGrath S, Campbell B, Lee H, Herdy J R, Gonçalves J T, Toda T, Kim Y, Winkler J, Yao J, Hetzer M W, Gage F H (2015). Directly reprogrammed human neurons retain aging-associated transcriptomic signatures and reveal age-related nucleocytoplasmic defects. Cell Stem Cell, 17(6): 705–718
|
| 50 |
Miller J D, Ganat Y M, Kishinevsky S, Bowman R L, Liu B, Tu E Y, Mandal P K, Vera E, Shim J W, Kriks S, Taldone T, Fusaki N, Tomishima M J, Krainc D, Milner T A, Rossi D J, Studer L (2013). Human iPSC-based modeling of late-onset disease via progerin-induced aging. Cell Stem Cell, 13(6): 691–705
|
| 51 |
Muratore C R, Rice H C, Srikanth P, Callahan D G, Shin T, Benjamin L N, Walsh D M, Selkoe D J, Young-Pearse T L (2014). The familial Alzheimer’s disease APPV717I mutation alters APP processing and Tau expression in iPSC-derived neurons. Hum Mol Genet, 23(13): 3523–3536
|
| 52 |
Nakagawa M, Koyanagi M, Tanabe K, Takahashi K, Ichisaka T, Aoi T, Okita K, Mochiduki Y, Takizawa N, Yamanaka S (2008). Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol, 26(1): 101–106
|
| 53 |
Narsinh K H, Sun N, Sanchez-Freire V, Lee A S, Almeida P, Hu S, Jan T, Wilson K D, Leong D, Rosenberg J, Yao M, Robbins R C, Wu J C (2011). Single cell transcriptional profiling reveals heterogeneity of human induced pluripotent stem cells. J Clin Invest, 121(3): 1217–1221
|
| 54 |
Ohta E, Nihira T, Uchino A, Imaizumi Y, Okada Y, Akamatsu W, Takahashi K, Hayakawa H, Nagai M, Ohyama M, Ryo M, Ogino M, Murayama S, Takashima A, Nishiyama K, Mizuno Y, Mochizuki H, Obata F, Okano H 2015. I2020T mutant LRRK2 iPSC-derived neurons in the Sagamihara family exhibit increased Tau phosphorylation through the AKT/GSK-3 signaling pathway. Human Mol Genet, 24(17):4879–4900
|
| 55 |
Okita K, Ichisaka T, Yamanaka S (2007). Generation of germline-competent induced pluripotent stem cells. Nature, 448(7151): 313–317
|
| 56 |
Ooi L, Sidhu K, Poljak A, Sutherland G, O’Connor M D, Sachdev P, Münch G (2013). Induced pluripotent stem cells as tools for disease modelling and drug discovery in Alzheimer’s disease. J Neural Transm (Vienna), 120(1): 103–111
|
| 57 |
Pang Z P, Yang N, Vierbuchen T, Ostermeier A, Fuentes D R, Yang T Q, Citri A, Sebastiano V, Marro S, Südhof T C, Wernig M (2011). Induction of human neuronal cells by defined transcription factors. Nature, 476(7359): 220–223
|
| 58 |
Pasinelli P, Brown R H (2006). Molecular biology of amyotrophic lateral sclerosis: insights from genetics. Nat Rev Neurosci, 7(9): 710–723
|
| 59 |
Price J L, Ko A I, Wade M J, Tsou S K, McKeel D W, Morris J C (2001). Neuron number in the entorhinal cortex and CA1 in preclinical Alzheimer disease. Arch Neurol, 58(9): 1395–1402
|
| 60 |
Ring K L, An M C, Zhang N, O’Brien R N, Ramos E M, Gao F, Atwood R, Bailus B J, Melov S, Mooney S D, Coppola G, Ellerby L M, the RING (2015). Genomic analysis reveals disruption of striatal neuronal development and therapeutic targets in human Hungtinton's disease neural stem cells. Stem Cell Rep, 5(6): 1023–1038
|
| 61 |
Ring K L, Tong L M, Balestra M E, Javier R, Andrews-Zwilling Y, Li G, Walker D, Zhang W R, Kreitzer A C, Huang Y (2012). Direct reprogramming of mouse and human fibroblasts into multipotent neural stem cells with a single factor. Cell Stem Cell, 11(1): 100–109
|
| 62 |
Ryan S D, Dolatabadi N, Chan S F, Zhang X, Akhtar M W, Parker J, Soldner F, Sunico C R, Nagar S, Talantova M, Lee B, Lopez K, Nutter A, Shan B, Molokanova E, Zhang Y, Han X, Nakamura T, Masliah E, Yates J R 3rd, Nakanishi N, Andreyev A Y, Okamoto S, Jaenisch R, Ambasudhan R, Lipton S A (2013). Isogenic human iPSC Parkinson’s model shows nitrosative stress-induced dysfunction in MEF2-PGC1a transcription. Cell, 155(6): 1351–1364
|
| 63 |
Schuster J, Halvardson J, Pilar Lorenzo L, Ameur A, Sobol M, Raykova D, Annerén G, Feuk L, Dahl N (2015). Transcriptome profiling reveals degree of variability in induced pluripotent stem cell lines: Impact for human disease modeling. Cell Reprogram, 17(5): 327–337
|
| 64 |
Seibler P, Graziotto J, Jeong H, Simunovic F, Klein C, Krainc D (2011). Mitochondrial Parkin recruitment is impaired in neurons derived from mutant PINK1 induced pluripotent stem cells. J Neurosci, 31(16): 5970–5976
|
| 65 |
Silva J, Barrandon O, Nichols J, Kawaguchi J, Theunissen T W, Smith A (2008). Promotion of reprogramming to ground state pluripotency by signal inhibition. PLoS Biol, 6(10): e253
|
| 66 |
Soldner F, Hockemeyer D, Beard C, Gao Q, Bell G W, Cook E G, Hargus G, Blak A, Cooper O, Mitalipova M, Isacson O, Jaenisch R (2009). Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell, 136(5): 964–977
|
| 67 |
Soldner F, Laganière J, Cheng A W, Hockemeyer D, Gao Q, Alagappan R, Khurana V, Golbe L I, Myers R H, Lindquist S, Zhang L, Guschin D, Fong L K, Vu B J, Meng X, Urnov F D, Rebar E J, Gregory P D, Zhang H S, Jaenisch R (2011). Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations. Cell, 146(2): 318–331
|
| 68 |
Sommer C A, Christodoulou C, Gianotti-Sommer A, Shen S S, Sailaja B S, Hezroni H, Spira A, Meshorer E, Kotton D N, Mostoslavsky G (2012). Residual expression of reprogramming factors affects the transcriptional program and epigenetic signatures of induced pluripotent stem cells. PLoS ONE, 7(12): e51711
|
| 69 |
Sproul A, Jacob S, Paquet D, Ortiz-Virumbrales M, Campos B, Gandy S, Tessier-Lavigne M, Noggle S (2014). Using familial Alzheimer's disease and isogenic control IPSc-derived basal forebrain neurons to model AD. Alzheimers Dement, 10(4): 643–P644
|
| 70 |
Strong M J, Yang W (2011). The frontotemporal syndromes of ALS. Clinicopathological correlates. J Mol Neurosci, 45(3): 648–655
|
| 71 |
Su Y, Blazey T M, Owen C J, Christensen J J, Friedrichsen K, Joseph-Mathurin N, Wang Q, Hornbeck R C, Ances B M, Snyder A Z, Cash L A, Koeppe R A, Klunk W E, Galasko D, Brickman A M, McDade E, Ringman J M, Thompson P M, Saykin A J, Ghetti B, Sperling R A, Johnson K A, Salloway S P, Schofield P R, Masters C L, Villemagne V L, Fox N C, Förster S, Chen K, Reiman E M, Xiong C, Marcus D S, Weiner M W, Morris J C, Bateman R J, Benzinger T L, the Dominantly Inherited Alzheimer Network (2016). Quantitative amyloid imaging in autosomal dominant Alzheimer’s disease: Results from the DIAN study group. PLoS ONE, 11(3): e0152082
|
| 72 |
Suhr S T, Chang E A, Tjong J, Alcasid N, Perkins G A, Goissis M D, Ellisman M H, Perez G I, Cibelli J B (2010). Mitochondrial rejuvenation after induced pluripotency. PLoS ONE, 5(11): e14095
|
| 73 |
Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131(5): 861–872
|
| 74 |
Tanzi R E, Bertram L (2005). Twenty years of the Alzheimer’s disease amyloid hypothesis: a genetic perspective. Cell, 120(4): 545–555
|
| 75 |
Thatava T, Kudva Y C, Edukulla R, Squillace K, De Lamo J G, Khan Y K, Sakuma T, Ohmine S, Terzic A, Ikeda Y (2013). Intrapatient variations in type 1 diabetes-specific iPS cell differentiation into insulin-producing cells. Mol Ther, 21(1): 228–239
|
| 76 |
The Medical Research Council Cognitive Function and Ageing Study (MRC CFAS) (1998). Cognitive function and dementia in six areas of England and Wales: the distribution of MMSE and prevalence of GMS organicity level in the MRC CFA Study. Psychol Med, 28(2): 319–335
|
| 77 |
Tsai M S, Tangalos E G, Petersen R C, Smith G E, Schaid D J, Kokmen E, Ivnik R J, Thibodeau S N (1994). Apolipoprotein E: risk factor for Alzheimer disease. Am J Hum Genet, 54(4): 643–649
|
| 78 |
Vera E, Studer L (2015). When rejuvenation is a problem: challenges of modeling late-onset neurodegenerative disease. Development, 142(18): 3085–3089
|
| 79 |
Vierbuchen T, Ostermeier A, Pang Z P, Kokubu Y, Südhof T C, Wernig M (2010). Direct conversion of fibroblasts to functional neurons by defined factors. Nature, 463(7284): 1035–1041
|
| 80 |
Wapinski O L, Vierbuchen T, Qu K, Lee Q Y, Chanda S, Fuentes D R, Giresi P G, Ng Y H, Marro S, Neff N F, Drechsel D, Martynoga B, Castro D S, Webb A E, Südhof T C, Brunet A, Guillemot F, Chang H Y, Wernig M (2013). Hierarchical mechanisms for direct reprogramming of fibroblasts to neurons. Cell, 155(3): 621–635
|
| 81 |
West M J, Coleman P D, Flood D G, Troncoso J C (1994). Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer’s disease. Lancet, 344(8925): 769–772
|
| 82 |
Wilcock D M (2010). The usefulness and challenges of transgenic mouse models in the study of Alzheimer’s disease. CNS Neurol Disord Drug Targets, 9(4): 386–394
|
| 83 |
Yagi T, Ito D, Okada Y, Akamatsu W, Nihei Y, Yoshizaki T, Yamanaka S, Okano H, Suzuki N (2011). Modeling familial Alzheimer’s disease with induced pluripotent stem cells. Hum Mol Genet, 20(23): 4530–4539
|
| 84 |
Yoo A S, Sun A X, Li L, Shcheglovitov A, Portmann T, Li Y, Lee-Messer C, Dolmetsch R E, Tsien R W, Crabtree G R (2011). MicroRNA-mediated conversion of human fibroblasts to neurons. Nature, 476(7359): 228–231
|
| 85 |
Zhou W, Freed C R (2009). Adenoviral gene delivery can reprogram human fibroblasts to induced pluripotent stem cells. Stem Cells, 27(11): 2667–2674
|
/
| 〈 |
|
〉 |