A Human Embryonic Stem Cell Model of Aβ-Dependent Chronic Progressive Neurodegeneration.
Alzheimer’s disease
Alzheimer’s model
amyloid-beta
neurodegeneration
stem cells
Journal
Frontiers in neuroscience
ISSN: 1662-4548
Titre abrégé: Front Neurosci
Pays: Switzerland
ID NLM: 101478481
Informations de publication
Date de publication:
2019
2019
Historique:
received:
22
05
2019
accepted:
05
09
2019
entrez:
17
10
2019
pubmed:
17
10
2019
medline:
17
10
2019
Statut:
epublish
Résumé
We describe the construction and phenotypic analysis of a human embryonic stem cell model of progressive Aβ-dependent neurodegeneration (ND) with potential relevance to Alzheimer's disease (AD). We modified one allele of the normal APP locus to directly express a secretory form of Aβ40 or Aβ42, enabling expression from this edited allele to bypass the normal amyloidogenic APP processing pathway. Following neuronal differentiation, edited cell lines specifically accumulate intracellular aggregated/oligomeric Aβ, exhibit a synaptic deficit, and have an abnormal accumulation of endolysosomal vesicles. Edited cultures progress to a stage of overt ND. All phenotypes appear at earlier culture times for Aβ42 relative to Aβ40. Whole transcriptome RNA-Seq analysis identified 23 up and 70 down regulated genes (differentially expressed genes) with similar directional fold change but larger absolute values in the Aβ42 samples suggesting common underlying pathogenic mechanisms. Pathway/annotation analysis suggested that down regulation of extracellular matrix and cilia functions is significantly overrepresented. This cellular model could be useful for uncovering mechanisms directly linking Aβ to neuronal death and as a tool to screen for new therapeutic agents that slow or prevent human ND.
Identifiants
pubmed: 31616241
doi: 10.3389/fnins.2019.01007
pmc: PMC6763609
doi:
Types de publication
Journal Article
Langues
eng
Pagination
1007Informations de copyright
Copyright © 2019 Ubina, Magallanes, Srivastava, Warden, Yee and Salvaterra.
Références
Am J Pathol. 2000 Jul;157(1):277-86
pubmed: 10880397
Cell. 2016 Jun 30;166(1):193-208
pubmed: 27293189
Neuron. 2009 Aug 13;63(3):287-303
pubmed: 19679070
Hum Mol Genet. 2014 Jul 1;23(13):3523-36
pubmed: 24524897
J Neurosci. 2012 Jan 25;32(4):1273-83
pubmed: 22279212
J Biol Chem. 2011 Jul 8;286(27):24264-74
pubmed: 21606494
Neuron. 2005 Jul 21;47(2):191-199
pubmed: 16039562
J Neurochem. 2016 Oct;139 Suppl 2:237-252
pubmed: 27255958
Neurology. 2006 Jan 24;66(2 Suppl 1):S69-73
pubmed: 16432149
Neuron. 2003 Oct 9;40(2):401-13
pubmed: 14556717
JAMA. 1989 Apr 7;261(13):1916-9
pubmed: 2926927
Expert Opin Drug Discov. 2012 Apr;7(4):281-97
pubmed: 22458501
Stem Cell Reports. 2017 Dec 12;9(6):1868-1884
pubmed: 29153990
Neuron. 2018 Jun 27;98(6):1141-1154.e7
pubmed: 29861287
Curr Biol. 2009 Jul 14;19(13):R526-35
pubmed: 19602418
J Neurosci. 2008 Jul 2;28(27):6926-37
pubmed: 18596167
Mol Cell Neurosci. 2004 Jul;26(3):365-75
pubmed: 15234342
Neuron. 2014 May 7;82(3):511-21
pubmed: 24811376
Nat Commun. 2012;3:1009
pubmed: 22910355
Am J Pathol. 2006 Jan;168(1):184-94
pubmed: 16400022
Cell Mol Life Sci. 2016 Oct;73(19):3693-709
pubmed: 27154043
Nucleic Acids Res. 2011 Jul;39(12):e82
pubmed: 21493687
EMBO Mol Med. 2016 Jun 01;8(6):595-608
pubmed: 27025652
Nat Rev Neurosci. 2007 Jul;8(7):499-509
pubmed: 17551515
Sci Rep. 2018 Mar 9;8(1):4282
pubmed: 29523845
Cell. 1995 May 19;81(4):525-31
pubmed: 7758106
Mol Neurodegener. 2014 Nov 18;9:51
pubmed: 25407337
Nature. 2014 Nov 13;515(7526):274-8
pubmed: 25307057
Nat Protoc. 2015 Jul;10(7):985-1006
pubmed: 26068894
Biochim Biophys Acta. 2001 Jul 27;1537(1):58-62
pubmed: 11476963
ASN Neuro. 2014 Mar 12;6(2):null
pubmed: 24521233
Cell. 1988 Feb 26;52(4):487-501
pubmed: 3257719
Nat Neurosci. 2012 Jan 29;15(3):349-57
pubmed: 22286176
J Cell Mol Med. 2009 Mar;13(3):412-21
pubmed: 19374683
Acta Neuropathol. 2017 Feb;133(2):155-175
pubmed: 28025715
Sci Rep. 2016 Jul 07;6:29200
pubmed: 27383650
Alzheimers Res Ther. 2014 Jul 03;6(4):37
pubmed: 25024750
Brain Pathol. 2010 Mar;20(2):468-80
pubmed: 19725829
BMC Genomics. 2012 Sep 04;13:451
pubmed: 22947103
Nat Rev Neurosci. 2016 Apr;17(4):251-60
pubmed: 26988744
Nat Rev Neurosci. 2007 Sep;8(9):663-72
pubmed: 17684513
Mol Cell Neurosci. 2016 Jun;73:13-31
pubmed: 26657644
Alzheimers Res Ther. 2016 Sep 20;8:39
pubmed: 27646601
Trends Mol Med. 2010 Jun;16(6):287-94
pubmed: 20537952
Neurobiol Aging. 1995 May-Jun;16(3):285-98; discussion 298-304
pubmed: 7566338
Acta Neuropathol. 2018 Dec;136(6):901-917
pubmed: 30362029
Science. 1993 Aug 13;261(5123):921-3
pubmed: 8346443
Biochem J. 2016 Jul 15;473(14):1977-93
pubmed: 27407168
Mol Neurodegener. 2017 May 26;12(1):43
pubmed: 28549481
J Neurosci. 2004 Jul 21;24(29):6629-37
pubmed: 15269275
Nat Methods. 2012 Jun 28;9(7):676-82
pubmed: 22743772
Nat Rev Mol Cell Biol. 2007 Feb;8(2):101-12
pubmed: 17245412
Cell Stem Cell. 2013 Apr 4;12(4):487-96
pubmed: 23434393
PLoS One. 2016 Sep 29;11(9):e0163072
pubmed: 27684569
Nat Neurosci. 2018 Jul;21(7):941-951
pubmed: 29950669
Cold Spring Harb Perspect Biol. 2012 Oct 01;4(10):null
pubmed: 22983160
FASEB J. 2017 Jul;31(7):2729-2743
pubmed: 28663518
Acta Neuropathol. 2010 May;119(5):523-41
pubmed: 20354705
Cell Rep. 2013 Nov 27;5(4):974-85
pubmed: 24239350
Alzheimers Res Ther. 2017 Jun 13;9(1):42
pubmed: 28610595
Cold Spring Harb Perspect Med. 2012 Feb;2(2):a006288
pubmed: 22355794
Trends Neurosci. 2017 Jun;40(6):347-357
pubmed: 28494972
EMBO J. 2017 Sep 1;36(17):2473-2487
pubmed: 28768718
Genome Med. 2011 Jul 27;3(7):49
pubmed: 21867573
Mol Neurodegener. 2006 Jul 03;1:5
pubmed: 16930452
PLoS One. 2014 Sep 03;9(9):e106576
pubmed: 25184295
Neurobiol Dis. 2010 May;38(2):167-72
pubmed: 20097287
Nat Neurosci. 2015 Jun;18(6):800-6
pubmed: 26007213
Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6623-8
pubmed: 15069204
Prog Neurobiol. 2014 Jan;112:24-49
pubmed: 24211851
Sci Rep. 2017 Dec 19;7(1):17762
pubmed: 29259249
J Neurosci. 2007 Jan 17;27(3):627-33
pubmed: 17234594
Proc Natl Acad Sci U S A. 2004 Jul 6;101(27):10000-5
pubmed: 15220480
J Alzheimers Dis. 2012;28(4):897-904
pubmed: 22112547
Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20324-9
pubmed: 19910533
Hum Mol Genet. 2012 Oct 15;21(R1):R82-9
pubmed: 22865875
Nat Med. 2018 May;24(5):647-657
pubmed: 29632371
J Biol Chem. 1999 Jun 25;274(26):18777-84
pubmed: 10373494
Nature. 2012 Jan 25;482(7384):216-20
pubmed: 22278060
Trends Cell Biol. 2015 Jan;25(1):46-53
pubmed: 25172552
Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):2173-8
pubmed: 14769913
Mol Psychiatry. 2011 Sep;16(9):903-7
pubmed: 21556001
Neurobiol Aging. 2004 Nov-Dec;25(10):1263-72
pubmed: 15465622
Nat Neurosci. 2014 May;17(5):661-3
pubmed: 24728269
J Neurochem. 2010 Nov;115(4):873-84
pubmed: 20412390
PLoS One. 2016 Sep 13;11(9):e0161969
pubmed: 27622770
Cell. 2010 Apr 30;141(3):497-508
pubmed: 20434987
Traffic. 2012 Jun;13(6):759-70
pubmed: 22269004
Cell. 2016 Feb 11;164(4):603-15
pubmed: 26871627
Nat Med. 2003 Apr;9(4):453-7
pubmed: 12612547
Sci Data. 2016 Oct 11;3:160089
pubmed: 27727239
Mol Cells. 2013 Oct;36(4):288-303
pubmed: 24048681
PLoS One. 2009;4(1):e4201
pubmed: 19145255
Cell Rep. 2013 Oct 17;5(1):61-9
pubmed: 24095740
Alzheimers Res Ther. 2010 Jul 14;2(4):12
pubmed: 20642866
Nat Genet. 1995 Jan;9(1):21-30
pubmed: 7704018
Lancet. 2016 Jul 30;388(10043):505-17
pubmed: 26921134
Neurobiol Dis. 2010 Feb;37(2):294-306
pubmed: 19781645
J Cell Biol. 2019 Feb 4;218(2):644-663
pubmed: 30626721
Neuron. 2017 Mar 8;93(5):1066-1081.e8
pubmed: 28238547
Neurobiol Dis. 2008 Jul;31(1):145-58
pubmed: 18571100
J Biol Chem. 1995 Jun 16;270(24):14786-92
pubmed: 7782344
Brain Struct Funct. 2010 Mar;214(2-3):245-62
pubmed: 19967412
J Neurosci. 2013 Jan 9;33(2):574-86
pubmed: 23303937
Biochemistry. 2000 Sep 5;39(35):10831-9
pubmed: 10978169
Neuron. 2010 Jun 10;66(5):631-45
pubmed: 20547123
Cold Spring Harb Perspect Med. 2012 Jul;2(7):a006338
pubmed: 22762015
Cold Spring Harb Perspect Med. 2012 May;2(5):a006270
pubmed: 22553493
Sci Transl Med. 2012 Mar 7;4(124):124ra29
pubmed: 22344463
J Intern Med. 2014 Mar;275(3):251-83
pubmed: 24605808
Cell. 2013 Apr 25;153(3):707-20
pubmed: 23622250
Nat Protoc. 2008;3(10):1550-8
pubmed: 18802436
Alzheimers Res Ther. 2013 Aug 27;5(4):39
pubmed: 23981712
Neuron. 2017 Dec 6;96(5):1024-1032.e3
pubmed: 29216449
PLoS One. 2010 Dec 17;5(12):e15600
pubmed: 21179413