APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer's disease patient iPSC-derived cerebral organoids.

Tytuł:: APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer's disease patient iPSC-derived cerebral organoids.
Autorzy:: Zhao J; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.; Center for Regenerative Medicine, Neuroregeneration Lab, Mayo Clinic, Jacksonville, FL, 32224, USA.
Fu Y; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
Yamazaki Y; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
Ren Y; Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, 32224, USA.
Davis MD; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.; Center for Regenerative Medicine, Neuroregeneration Lab, Mayo Clinic, Jacksonville, FL, 32224, USA.
Liu CC; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
Lu W; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.; Center for Regenerative Medicine, Neuroregeneration Lab, Mayo Clinic, Jacksonville, FL, 32224, USA.
Wang X; Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, 32224, USA.
Chen K; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
Cherukuri Y; Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, 32224, USA.
Jia L; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
Martens YA; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
Job L; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.; Center for Regenerative Medicine, Neuroregeneration Lab, Mayo Clinic, Jacksonville, FL, 32224, USA.
Shue F; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
Nguyen TT; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
Younkin SG; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
Graff-Radford NR; Department of Neurology, Mayo Clinic, Jacksonville, FL, 32224, USA.
Wszolek ZK; Department of Neurology, Mayo Clinic, Jacksonville, FL, 32224, USA.
Brafman DA; School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, 85287, USA.
Asmann YW; Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, 32224, USA.
Ertekin-Taner N; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.; Department of Neurology, Mayo Clinic, Jacksonville, FL, 32224, USA.
Kanekiyo T; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.; Center for Regenerative Medicine, Neuroregeneration Lab, Mayo Clinic, Jacksonville, FL, 32224, USA.
Bu G; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA. .; Center for Regenerative Medicine, Neuroregeneration Lab, Mayo Clinic, Jacksonville, FL, 32224, USA. .
Źródło:: Nature communications [Nat Commun] 2020 Nov 02; Vol. 11 (1), pp. 5540. Date of Electronic Publication: 2020 Nov 02.
Typ publikacji:: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Original Publication: [London] : Nature Pub. Group
MeSH Terms:: Alzheimer Disease/*metabolism
Apolipoprotein E3/*genetics
Apolipoprotein E3/*metabolism
Induced Pluripotent Stem Cells/*metabolism
Organoids/*metabolism
Synapses/*metabolism
Alzheimer Disease/genetics ; Apolipoprotein E4/genetics ; Gene Expression Regulation ; Genotype ; Humans ; Organoids/pathology ; RNA/metabolism ; Transcriptome
References:: Selkoe, D. J. Toward a remembrance of things past: deciphering Alzheimer disease. Harvey Lect. 99, 23–45 (2003). (PMID: 15984550)
Jack, C. R. Jr. et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol. 9, 119–128 (2010). (PMID: 20083042281984010.1016/S1474-4422(09)70299-6)
DeTure, M. A. & Dickson, D. W. The neuropathological diagnosis of Alzheimer’s disease. Mol. Neurodegener. 14, 32 (2019). (PMID: 31375134667948410.1186/s13024-019-0333-5)
Corder, E. H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261, 921–923 (1993). (PMID: 834644310.1126/science.8346443)
Kim, J., Basak, J. M. & Holtzman, D. M. The role of apolipoprotein E in Alzheimer’s disease. Neuron 63, 287–303 (2009). (PMID: 19679070304444610.1016/j.neuron.2009.06.026)
Liu, C. C., Liu, C. C., Kanekiyo, T., Xu, H. & Bu, G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat. Rev. Neurol. 9, 106–118 (2013). (PMID: 23296339372671910.1038/nrneurol.2012.263)
Yu, J. T., Tan, L. & Hardy, J. Apolipoprotein E in Alzheimer’s disease: an update. Annu Rev. Neurosci. 37, 79–100 (2014). (PMID: 2482131210.1146/annurev-neuro-071013-014300)
Najm, R., Jones, E. A. & Huang, Y. Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease. Mol. Neurodegener. 14, 24 (2019). (PMID: 31186040655877910.1186/s13024-019-0324-6)
Huynh, T. V., Davis, A. A., Ulrich, J. D., Holtzman, D. M. & Apolipoprotein, E. and Alzheimer’s disease: the influence of apolipoprotein E on amyloid-beta and other amyloidogenic proteins. J. Lipid Res. 58, 824–836 (2017). (PMID: 28246336540861910.1194/jlr.R075481)
Huang, Y. & Mucke, L. Alzheimer mechanisms and therapeutic strategies. Cell 148, 1204–1222 (2012). (PMID: 22424230331907110.1016/j.cell.2012.02.040)
Golde, T. E., Schneider, L. S. & Koo, E. H. Anti-abeta therapeutics in Alzheimer’s disease: the need for a paradigm shift. Neuron 69, 203–213 (2011). (PMID: 21262461305890610.1016/j.neuron.2011.01.002)
Ashe, K. H. & Zahs, K. R. Probing the biology of Alzheimer’s disease in mice. Neuron 66, 631–645 (2010). (PMID: 20547123295642010.1016/j.neuron.2010.04.031)
Israel, M. A. et al. Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature 482, 216–220 (2012). (PMID: 22278060333898510.1038/nature10821)
Yagi, T. et al. Modeling familial Alzheimer’s disease with induced pluripotent stem cells. Hum. Mol. Genet. 20, 4530–4539 (2011). (PMID: 2190035710.1093/hmg/ddr394)
Kondo, T. et al. Modeling Alzheimer’s disease with iPSCs reveals stress phenotypes associated with intracellular Abeta and differential drug responsiveness. Cell Stem Cell 12, 487–496 (2013). (PMID: 2343439310.1016/j.stem.2013.01.009)
Liu, Q. et al. Effect of potent gamma-secretase modulator in human neurons derived from multiple presenilin 1-induced pluripotent stem cell mutant carriers. JAMA Neurol. 71, 1481–1489 (2014). (PMID: 25285942437463710.1001/jamaneurol.2014.2482)
Centeno, E. G. Z., Cimarosti, H. & Bithell, A. 2D versus 3D human induced pluripotent stem cell-derived cultures for neurodegenerative disease modelling. Mol. Neurodegener. 13, 27 (2018). (PMID: 29788997596471210.1186/s13024-018-0258-4)
Muratore, C. R. et al. The familial Alzheimer’s disease APPV717I mutation alters APP processing and Tau expression in iPSC-derived neurons. Hum. Mol. Genet. 23, 3523–3536 (2014). (PMID: 24524897404930710.1093/hmg/ddu064)
Wang, C. et al. Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector. Nat. Med. 24, 647–657 (2018). (PMID: 29632371594815410.1038/s41591-018-0004-z)
Lancaster, M. A. et al. Cerebral organoids model human brain development and microcephaly. Nature 501, 373–379 (2013). (PMID: 2399568510.1038/nature12517)
Lancaster, M. A. & Knoblich, J. A. Generation of cerebral organoids from human pluripotent stem cells. Nat. Protoc. 9, 2329–2340 (2014). (PMID: 25188634416065310.1038/nprot.2014.158)
Renner, M. et al. Self-organized developmental patterning and differentiation in cerebral organoids. EMBO J. 36, 1316–1329 (2017). (PMID: 28283582543022510.15252/embj.201694700)
Okita, K. et al. A more efficient method to generate integration-free human iPS cells. Nat. Methods 8, 409–412 (2011). (PMID: 10.1038/nmeth.159121460823)
Zhao, J. et al. APOE epsilon4/epsilon4 diminishes neurotrophic function of human iPSC-derived astrocytes. Hum. Mol. Genet. 26, 2690–2700 (2017). (PMID: 28444230588609110.1093/hmg/ddx155)
Brookhouser, N., Zhang, P., Caselli, R., Kim, J. J. & Brafman, D. A. Generation and characterization of two human induced pluripotent stem cell (hiPSC) lines homozygous for the Apolipoprotein e4 (APOE4) risk variant-Alzheimer’s disease (ASUi005-A) and healthy non-demented control (ASUi006-A). Stem Cell Res. 32, 145–149 (2018). (PMID: 30296667621786010.1016/j.scr.2018.09.007)
Brookhouser, N., Zhang, P., Caselli, R., Kim, J. J. & Brafman, D. A. Generation and characterization of human induced pluripotent stem cell (hiPSC) lines from an Alzheimer’s disease (ASUi001-A) and non-demented control (ASUi002-A) patient homozygous for the Apolipoprotein e4 (APOE4) risk variant. Stem Cell Res. 24, 160–163 (2017). (PMID: 2903488610.1016/j.scr.2017.06.003)
Yamazaki, Y. et al. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat. Rev. Neurol. 15, 501–518 (2019).
Lin, Y. T. et al. APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC-derived brain cell types. Neuron 98, 1141–1154.e1147 (2018). (PMID: 29861287602375110.1016/j.neuron.2018.05.008)
Niewidok, B. et al. Single-molecule imaging reveals dynamic biphasic partition of RNA-binding proteins in stress granules. J. Cell Biol. 217, 1303–1318 (2018). (PMID: 29463567588150610.1083/jcb.201709007)
Van Treeck, B. et al. RNA self-assembly contributes to stress granule formation and defining the stress granule transcriptome. Proc. Natl Acad. Sci. USA 115, 2734–2739 (2018). (PMID: 29483269585656110.1073/pnas.1800038115)
Gaugler, J. et al. 2019 Alzheimer’s disease facts and figures. Alzheimer’s & Dementia 15, 321–387 (2019).
Jack, C. R. Jr. et al. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement 14, 535–562 (2018). (PMID: 29653606595862510.1016/j.jalz.2018.02.018)
Quadrato, G. et al. Cell diversity and network dynamics in photosensitive human brain organoids. Nature 545, 48–53 (2017). (PMID: 28445462565934110.1038/nature22047)
Choi, S. H. et al. A three-dimensional human neural cell culture model of Alzheimer’s disease. Nature 515, 274–278 (2014). (PMID: 25307057436600710.1038/nature13800)
Gonzalez, C. et al. Modeling amyloid beta and tau pathology in human cerebral organoids. Mol. Psychiatry 23, 2363–2374 (2018). (PMID: 30171212659470410.1038/s41380-018-0229-8)
Balez, R. et al. Neuroprotective effects of apigenin against inflammation, neuronal excitability and apoptosis in an induced pluripotent stem cell model of Alzheimer’s disease. Sci. Rep. 6, 31450 (2016). (PMID: 27514990498184510.1038/srep31450)
Raja, W. K. et al. Self-organizing 3D human neural tissue derived from induced pluripotent stem cells recapitulate Alzheimer’s disease phenotypes. PLoS ONE 11, e0161969 (2016). (PMID: 27622770502136810.1371/journal.pone.0161969)
Alonso, A. C., Zaidi, T., Grundke-Iqbal, I. & Iqbal, K. Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease. Proc. Natl Acad. Sci. USA 91, 5562–5566 (1994). (PMID: 82025284403610.1073/pnas.91.12.5562)
Mi, K. & Johnson, G. V. The role of tau phosphorylation in the pathogenesis of Alzheimer’s disease. Curr. Alzheimer Res 3, 449–463 (2006). (PMID: 1716864410.2174/156720506779025279)
Meeter, L. H., Kaat, L. D., Rohrer, J. D. & van Swieten, J. C. Imaging and fluid biomarkers in frontotemporal dementia. Nat. Rev. Neurol. 13, 406–419 (2017). (PMID: 2862176810.1038/nrneurol.2017.75)
Ochalek, A. et al. Neurons derived from sporadic Alzheimer’s disease iPSCs reveal elevated TAU hyperphosphorylation, increased amyloid levels, and GSK3B activation. Alzheimers Res. Ther. 9, 90 (2017). (PMID: 29191219570997710.1186/s13195-017-0317-z)
Shi, Y. et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549, 523–527 (2017). (PMID: 28959956564121710.1038/nature24016)
Meyer, K. et al. REST and neural gene network dysregulation in iPSC models of Alzheimer’s disease. Cell Rep. 26, 1112–1127.e1119 (2019). (PMID: 30699343638619610.1016/j.celrep.2019.01.023)
Nussbacher, J. K., Tabet, R., Yeo, G. W. & Lagier-Tourenne, C. Disruption of RNA metabolism in neurological diseases and emerging therapeutic interventions. Neuron 102, 294–320 (2019). (PMID: 30998900654512010.1016/j.neuron.2019.03.014)
Liu, E. Y., Cali, C. P. & Lee, E. B. RNA metabolism in neurodegenerative disease. Dis. Model Mech. 10, 509–518 (2017). (PMID: 28468937545117310.1242/dmm.028613)
Johnson, E. C. B. et al. Deep proteomic network analysis of Alzheimer’s disease brain reveals alterations in RNA binding proteins and RNA splicing associated with disease. Mol. Neurodegener. 13, 52 (2018). (PMID: 30286791617270710.1186/s13024-018-0282-4)
Vanderweyde, T. et al. Contrasting pathology of the stress granule proteins TIA-1 and G3BP in tauopathies. J. Neurosci. 32, 8270–8283 (2012). (PMID: 22699908340238010.1523/JNEUROSCI.1592-12.2012)
Maziuk, B. F. et al. RNA binding proteins co-localize with small tau inclusions in tauopathy. Acta Neuropathol. Commun. 6, 71 (2018). (PMID: 30068389606970510.1186/s40478-018-0574-5)
Brunello, C. A., Yan, X. & Huttunen, H. J. Internalized Tau sensitizes cells to stress by promoting formation and stability of stress granules. Sci. Rep. 6, 30498 (2016). (PMID: 27460788496231910.1038/srep30498)
Brookman, K. W. et al. ERCC4 (XPF) encodes a human nucleotide excision repair protein with eukaryotic recombination homologs. Mol. Cell Biol. 16, 6553–6562 (1996). (PMID: 888768423165710.1128/MCB.16.11.6553)
Calses, P. C. et al. DGCR8 mediates repair of UV-induced DNA damage independently of RNA processing. Cell Rep. 19, 162–174 (2017). (PMID: 28380355542378510.1016/j.celrep.2017.03.021)
Shen, A. et al. EBF1-mediated upregulation of ribosome assembly factor PNO1 contributes to cancer progression by negatively regulating the p53 signaling pathway. Cancer Res. 79, 2257–2270 (2019). (PMID: 3086272010.1158/0008-5472.CAN-18-3238)
Zuo, D., Subjeck, J. & Wang, X. Y. Unfolding the role of large heat shock proteins: new insights and therapeutic implications. Front. Immunol. 7, 75 (2016). (PMID: 26973652477173210.3389/fimmu.2016.00075)
Mansour, A. A. et al. An in vivo model of functional and vascularized human brain organoids. Nat. Biotechnol. 36, 432–441 (2018). (PMID: 29658944633120310.1038/nbt.4127)
Abreu, C. M. et al. Microglia increase inflammatory responses in iPSC-derived human brainspheres. Front. Microbiol. 9, 2766 (2018). (PMID: 30619100629631710.3389/fmicb.2018.02766)
Ormel, P. R. et al. Microglia innately develop within cerebral organoids. Nat. Commun. 9, 4167 (2018). (PMID: 30301888617748510.1038/s41467-018-06684-2)
Linkous, A. et al. Modeling patient-derived glioblastoma with cerebral organoids. Cell Rep. 26, 3203–3211.e3205 (2019). (PMID: 30893594662575310.1016/j.celrep.2019.02.063)
Wren, M. C. et al. Frontotemporal dementia-associated N279K tau mutant disrupts subcellular vesicle trafficking and induces cellular stress in iPSC-derived neural stem cells. Mol. Neurodegener. 10, 46 (2015). (PMID: 26373282457264510.1186/s13024-015-0042-7)
Awe, J. P. et al. Putative immunogenicity expression profiling using human pluripotent stem cells and derivatives. Stem Cells Transl. Med. 4, 136–145 (2015). (PMID: 25575527430335510.5966/sctm.2014-0117)
Nimsanor, N. et al. Induced pluripotent stem cells (iPSCs) derived from a symptomatic carrier of a S305I mutation in the microtubule-associated protein tau (MAPT)-gene causing frontotemporal dementia. Stem Cell Res. 17, 564–567 (2016). (PMID: 2778941110.1016/j.scr.2016.10.006)
Kalari, K. R. et al. MAP-RSeq: Mayo analysis pipeline for RNA sequencing. BMC Bioinforma. 15, 224 (2014). (PMID: 10.1186/1471-2105-15-224)
Hansen, K. D., Irizarry, R. A. & Wu, Z. Removing technical variability in RNA-seq data using conditional quantile normalization. Biostatistics 13, 204–216 (2012). (PMID: 22285995329782510.1093/biostatistics/kxr054)
McKenzie, A. T. et al. Brain cell type specific gene expression and co-expression network architectures. Sci. Rep. 8, 8868 (2018). (PMID: 29892006599580310.1038/s41598-018-27293-5)
Newman, A. M. et al. Robust enumeration of cell subsets from tissue expression profiles. Nat. Methods 12, 453–457 (2015). (PMID: 25822800473964010.1038/nmeth.3337)
Zhang, Y. et al. Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron 89, 37–53 (2016). (PMID: 2668783810.1016/j.neuron.2015.11.013)
Chikina, M., Zaslavsky, E. & Sealfon, S. C. CellCODE: a robust latent variable approach to differential expression analysis for heterogeneous cell populations. Bioinformatics 31, 1584–1591 (2015). (PMID: 25583121442684110.1093/bioinformatics/btv015)
Langfelder, P. & Horvath, S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinforma. 9, 559 (2008). (PMID: 10.1186/1471-2105-9-559)
Hu, Z. et al. VisANT 4.0: integrative network platform to connect genes, drugs, diseases and therapies. Nucleic Acids Res. 41, W225–W231 (2013). (PMID: 23716640369207010.1093/nar/gkt401)
Grant Information:: P01 NS074969 United States NS NINDS NIH HHS; RF1 AG051504 United States AG NIA NIH HHS; R01 AG027924 United States AG NIA NIH HHS; R01 AG061796 United States AG NIA NIH HHS; R37 AG027924 United States AG NIA NIH HHS; U01 AG046139 United States AG NIA NIH HHS; P30 AG062677 United States AG NIA NIH HHS; RF1 AG046205 United States AG NIA NIH HHS; R01 AG066395 United States AG NIA NIH HHS; RF1 AG057181 United States AG NIA NIH HHS
Substance Nomenclature:: 0 (Apolipoprotein E3)
0 (Apolipoprotein E4)
0 (apolipoprotein E7, human)
63231-63-0 (RNA)
Entry Date(s):: Date Created: 20201103 Date Completed: 20201119 Latest Revision: 20220902
Update Code:: 20240105
PubMed Central ID:: PMC7608683
DOI:: 10.1038/s41467-020-19264-0
PMID:: 33139712
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APOE4 is the strongest genetic risk factor associated with late-onset Alzheimer's disease (AD). To address the underlying mechanism, we develop cerebral organoid models using induced pluripotent stem cells (iPSCs) with APOE ε3/ε3 or ε4/ε4 genotype from individuals with either normal cognition or AD dementia. Cerebral organoids from AD patients carrying APOE ε4/ε4 show greater apoptosis and decreased synaptic integrity. While AD patient-derived cerebral organoids have increased levels of Aβ and phosphorylated tau compared to healthy subject-derived cerebral organoids, APOE4 exacerbates tau pathology in both healthy subject-derived and AD patient-derived organoids. Transcriptomics analysis by RNA-sequencing reveals that cerebral organoids from AD patients are associated with an enhancement of stress granules and disrupted RNA metabolism. Importantly, isogenic conversion of APOE4 to APOE3 attenuates the APOE4-related phenotypes in cerebral organoids from AD patients. Together, our study using human iPSC-organoids recapitulates APOE4-related phenotypes and suggests APOE4-related degenerative pathways contributing to AD pathogenesis.

Comment in: Nat Rev Neurol. 2021 Jan;17(1):1. (PMID: 33219337)
Erratum in: Nat Commun. 2021 May 5;12(1):2707. (PMID: 33953196)

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