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Apolipoprotein E regulates lipid metabolism and α-synuclein pathology in human iPSC-derived cerebral organoids

Zhao, Jing, Lu, Wenyan, Ren, Yingxue, Fu, Yuan, Martens, Yuka A., Shue, Francis, Davis, Mary D., Wang, Xue, Chen, Kai, Li, Fuyao, Liu, Chia-Chen, Graff-Radford, Neill R., Wszolek, Zbigniew K., Younkin, Steven G., Brafman, David A., Ertekin-Taner, Nilüfer, Asmann, Yan W., Dickson, Dennis W., Xu, Ziying, Pan, Meixia, Han, Xianlin, Kanekiyo, Takahisa, Bu, Guojun·2021·Acta Neuropathologica
DOI 10.1007/s00401-021-02361-9PMC PMC8500881
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Abstract

APOE4 is a strong genetic risk factor for Alzheimer’s disease and Dementia with Lewy bodies; however, how its expression impacts pathogenic pathways in a human-relevant system is not clear. Here using human iPSC-derived cerebral organoid models, we find that APOE deletion increases α-synuclein (αSyn) accumulation accompanied with synaptic loss, reduction of GBA levels, lipid droplet accumulation and dysregulation of intracellular organelles. These phenotypes are partially rescued by exogenous apoE2 and apoE3, but not apoE4. Lipidomics analysis detects the increased fatty acid utilization and cholesterol ester accumulation in apoE-deficient cerebral organoids. Furthermore, APOE4 cerebral organoids have increased αSyn accumulation compared to those with APOE3. Carrying APOE4 also increases apoE association with Lewy bodies in postmortem brains from patients with Lewy body disease. Our findings reveal the predominant role of apoE in lipid metabolism and αSyn pathology in iPSC-derived cerebral organoids, providing mechanistic insights into how APOE4 drives the risk for synucleinopathies.

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  • Increased cholesterol levels are present in tandem with neuronal dysfunction and tau aggregation in several experimental models.

    “Using several experimental models, it has been shown that increased cholesterol levels are present in tandem with neuronal dysfunction and tau aggregation4,5,18–25.”

    From GRAMD1B is a regulator of lipid homeostasis, autophagic flux and phosphorylated tau (2025) · cites this paper as [23]

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Research works printed but not linked: 63

  1. Alzheimer’s Association (2020) 2020 Alzheimer’s disease facts and figures. Alzheimers Dement. https://doi.org/10.1002/alz.12068 · DOI · Paper page
  2. Alza NP, Iglesias Gonzalez PA, Conde MA, Uranga RM, Salvador GA (2019) Lipids at the crossroad of Alpha-Synuclein function and dysfunction: biological and pathological implications. Front Cell Neurosci 13:175. https://doi.org/10.3389/fncel.2019.00175 · DOI
  3. Arnaoutoglou NA, O’Brien JT, Underwood BR (2019) Dementia with Lewy bodies—from scientific knowledge to clinical insights. Nat Rev Neurol 15:103–112. https://doi.org/10.1038/s41582-018-0107-7 · DOI
  4. Bassil F, Brown HJ, Pattabhiraman S, Iwasyk JE, Maghames CM, Meymand ES et al (2020) Amyloid-beta (Abeta) plaques promote seeding and spreading of alpha-synuclein and Tau in a mouse model of lewy body disorders with Abeta pathology. Neuron 105(260–275):e266. https://doi.org/10.1016/j.neuron.2019.10.010 · DOI
  5. Belarbi K, Cuvelier E, Bonte MA, Desplanque M, Gressier B, Devos D et al (2020) Glycosphingolipids and neuroinflammation in Parkinson’s disease. Mol Neurodegener 15:59. https://doi.org/10.1186/s13024-020-00408-1 · DOI · Paper page
  6. Blanz J, Saftig P (2016) Parkinson’s disease: acid-glucocerebrosidase activity and alpha-synuclein clearance. J Neurochem 139(Suppl 1):198–215. https://doi.org/10.1111/jnc.13517 · DOI
  7. Chikina M, Zaslavsky E, Sealfon SC (2015) CellCODE: a robust latent variable approach to differential expression analysis for heterogeneous cell populations. Bioinformatics 31:1584–1591. https://doi.org/10.1093/bioinformatics/btv015 · DOI
  8. Davis AA, Inman CE, Wargel ZM, Dube U, Freeberg BM, Galluppi A et al (2020) APOE genotype regulates pathology and disease progression in synucleinopathy. Sci Transl Med. https://doi.org/10.1126/scitranslmed.aay3069 · DOI · Paper page
  9. den Brok MH, Raaijmakers TK, Collado-Camps E, Adema GJ (2018) Lipid droplets as immune modulators in myeloid cells. Trends Immunol 39:380–392. https://doi.org/10.1016/j.it.2018.01.012 · DOI · Paper page
  10. Dickson DW, Heckman MG, Murray ME, Soto AI, Walton RL, Diehl NN et al (2018) APOE epsilon4 is associated with severity of Lewy body pathology independent of Alzheimer pathology. Neurology 91:e1182–e1195. https://doi.org/10.1212/WNL.0000000000006212 · DOI · Paper page
  11. Do J, McKinney C, Sharma P, Sidransky E (2019) Glucocerebrosidase and its relevance to Parkinson disease. Mol Neurodegener 14:36. https://doi.org/10.1186/s13024-019-0336-2 · DOI
  12. Emamzadeh FN (2017) Role of Apolipoproteins and alpha-Synuclein in Parkinson’s Disease. J Mol Neurosci 62:344–355. https://doi.org/10.1007/s12031-017-0942-9 · DOI
  13. Emamzadeh FN, Allsop D (2017) alpha-Synuclein Interacts with Lipoproteins in Plasma. J Mol Neurosci 63:165–172. https://doi.org/10.1007/s12031-017-0967-0 · DOI
  14. Erskine D, Koss D, Korolchuk VI, Outeiro TF, Attems J, McKeith I (2021) Lipids, lysosomes and mitochondria: insights into Lewy body formation from rare monogenic disorders. Acta Neuropathol 141:511–526. https://doi.org/10.1007/s00401-021-02266-7 · DOI
  15. Galvin JE (2015) Improving the clinical detection of Lewy body dementia with the Lewy Body Composite Risk Score. Alzheimers Dement 1:316–324. https://doi.org/10.1016/j.dadm.2015.05.004 · DOI
  16. Gubern A, Barcelo-Torns M, Barneda D, Lopez JM, Masgrau R, Picatoste F et al (2009) JNK and ceramide kinase govern the biogenesis of lipid droplets through activation of group IVA phospholipase A2. J Biol Chem 284:32359–32369. https://doi.org/10.1074/jbc.M109.061515 · DOI
  17. Guerreiro R, Ross OA, Kun-Rodrigues C, Hernandez DG, Orme T, Eicher JD et al (2018) Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study. Lancet Neurol 17:64–74. https://doi.org/10.1016/S1474-4422(17)30400-3 · DOI · Paper page
  18. Han X (2016) Lipidomics: comprehensive mass spectrometry of lipids /Xianlin Han. Wiley, Hoboken · DOI
  19. Harris LA, Skinner JR, Wolins NE (2013) Imaging of neutral lipids and neutral lipid associated proteins. Methods Cell Biol 116:213–226. https://doi.org/10.1016/B978-0-12-408051-5.00011-5 · DOI · Paper page
  20. Hijaz BA, Volpicelli-Daley LA (2020) Initiation and propagation of alpha-synuclein aggregation in the nervous system. Mol Neurodegener 15:19. https://doi.org/10.1186/s13024-020-00368-6 · DOI
  21. Hu X, Xu B, Ge W (2017) The role of lipid bodies in the microglial aging process and related diseases. Neurochem Res 42:3140–3148. https://doi.org/10.1007/s11064-017-2351-4 · DOI · Paper page
  22. Hu Z, Chang Y-C, Wang Y, Huang C-L, Liu Y, Tian F et al (2013) VisANT 4.0: Integrative network platform to connect genes, drugs, diseases and therapies. Nucleic Acids Res 41:W225–W231. https://doi.org/10.1093/nar/gkt401 · DOI
  23. Huijbregts RP, Topalof L, Bankaitis VA (2000) Lipid metabolism and regulation of membrane trafficking. Traffic 1:195–202 · DOI
  24. Jellinger KA (2003) Neuropathological spectrum of synucleinopathies. Mov Disord 18(Suppl 6):S2-12. https://doi.org/10.1002/mds.10557 · DOI
  25. Jo S, Kim SO, Park KW, Lee SH, Hwang YS, Chung SJ (2021) The role of APOE in cognitive trajectories and motor decline in Parkinson’s disease. Sci Rep 11:7819. https://doi.org/10.1038/s41598-021-86483-w · DOI
  26. Kalari KR, Nair AA, Bhavsar JD, O’Brien DR, Davila JI, Bockol MA et al (2014) MAP-RSeq: mayo analysis pipeline for RNA sequencing. BMC Bioinformatics 15:224. https://doi.org/10.1186/1471-2105-15-224 · DOI
  27. Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C et al (2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet 45:1452–1458. https://doi.org/10.1038/ng.2802 · DOI · Paper page
  28. Lancaster MA, Knoblich JA (2014) Generation of cerebral organoids from human pluripotent stem cells. Nat Protoc 9:2329–2340. https://doi.org/10.1038/nprot.2014.158 · DOI · Paper page
  29. Langfelder P, Horvath S (2008) WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics 9:559. https://doi.org/10.1186/1471-2105-9-559 · DOI · Paper page
  30. Lashuel HA, Overk CR, Oueslati A, Masliah E (2013) The many faces of alpha-synuclein: from structure and toxicity to therapeutic target. Nat Rev Neurosci 14:38–48. https://doi.org/10.1038/nrn3406 · DOI
  31. Li J, Luo J, Liu L, Fu H, Tang L (2018) The genetic association between apolipoprotein E gene polymorphism and Parkinson disease: a meta-analysis of 47 studies. Medicine 97:e12884. https://doi.org/10.1097/MD.0000000000012884 · DOI
  32. Li Z, Shue F, Zhao N, Shinohara M, Bu G (2020) APOE2: protective mechanism and therapeutic implications for Alzheimer’s disease. Mol Neurodegener 15:63. https://doi.org/10.1186/s13024-020-00413-4 · DOI · Paper page
  33. Liu CC, Yamazaki Y, Heckman MG, Martens YA, Jia L, Yamazaki A et al (2020) Tau and apolipoprotein E modulate cerebrovascular tight junction integrity independent of cerebral amyloid angiopathy in Alzheimer’s disease. Alzheimers Dement 16:1372–1383. https://doi.org/10.1002/alz.12104 · DOI
  34. Mauch DH, Nagler K, Schumacher S, Goritz C, Muller EC, Otto A et al (2001) CNS synaptogenesis promoted by glia-derived cholesterol. Science 294:1354–1357. https://doi.org/10.1126/science.294.5545.1354 · DOI · Paper page
  35. Mazzulli JR, Xu YH, Sun Y, Knight AL, McLean PJ, Caldwell GA et al (2011) Gaucher disease glucocerebrosidase and alpha-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 146:37–52. https://doi.org/10.1016/j.cell.2011.06.001 · DOI · Paper page
  36. Mazzulli JR, Zunke F, Tsunemi T, Toker NJ, Jeon S, Burbulla LF et al (2016) Activation of beta-Glucocerebrosidase Reduces Pathological alpha-Synuclein and Restores Lysosomal Function in Parkinson’s Patient Midbrain Neurons. J Neurosci 36:7693–7706. https://doi.org/10.1523/JNEUROSCI.0628-16.2016 · DOI
  37. Meade RM, Fairlie DP, Mason JM (2019) Alpha-synuclein structure and Parkinson’s disease—lessons and emerging principles. Mol Neurodegener 14:29. https://doi.org/10.1186/s13024-019-0329-1 · DOI · Paper page
  38. Morikawa M, Fryer JD, Sullivan PM, Christopher EA, Wahrle SE, DeMattos RB et al (2005) Production and characterization of astrocyte-derived human apolipoprotein E isoforms from immortalized astrocytes and their interactions with amyloid-beta. Neurobiol Dis 19:66–76. https://doi.org/10.1016/j.nbd.2004.11.005 · DOI · Paper page
  39. Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y et al (2015) Robust enumeration of cell subsets from tissue expression profiles. Nat Meth 12: 453–457. https://doi.org/10.1038/nmeth.3337. http://www.nature.com/nmeth/journal/v12/n5/abs/nmeth.3337.html#supplementary-information · DOI · Paper page
  40. Nguyen TB, Louie SM, Daniele JR, Tran Q, Dillin A, Zoncu R et al (2017) DGAT1-dependent lipid droplet biogenesis protects mitochondrial function during starvation-induced autophagy. Dev Cell 42(9–21):e25. https://doi.org/10.1016/j.devcel.2017.06.003 · DOI · Paper page
  41. Nimsanor N, Jorring I, Rasmussen MA, Clausen C, Mau-Holzmann UA, Kitiyanant N et al (2016) 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. https://doi.org/10.1016/j.scr.2016.10.006 · DOI
  42. Okita K, Matsumura Y, Sato Y, Okada A, Morizane A, Okamoto S et al (2011) A more efficient method to generate integration-free human iPS cells. Nat Methods 8:409–412. https://doi.org/10.1038/nmeth.1591 · DOI · Paper page
  43. Outeiro TF, Koss DJ, Erskine D, Walker L, Kurzawa-Akanbi M, Burn D et al (2019) Dementia with Lewy bodies: an update and outlook. Mol Neurodegener 14:5. https://doi.org/10.1186/s13024-019-0306-8 · DOI · Paper page
  44. Pols MS, ten Brink C, Gosavi P, Oorschot V, Klumperman J (2013) The HOPS proteins hVps41 and hVps39 are required for homotypic and heterotypic late endosome fusion. Traffic 14:219–232. https://doi.org/10.1111/tra.12027 · DOI
  45. Rambold AS, Cohen S, Lippincott-Schwartz J (2015) Fatty acid trafficking in starved cells: regulation by lipid droplet lipolysis, autophagy, and mitochondrial fusion dynamics. Dev Cell 32:678–692. https://doi.org/10.1016/j.devcel.2015.01.029 · DOI · Paper page
  46. Rees DC, Johnson E, Lewinson O (2009) ABC transporters: the power to change. Nat Rev Mol Cell Biol 10:218–227. https://doi.org/10.1038/nrm2646 · DOI
  47. Renner M, Lancaster MA, Bian S, Choi H, Ku T, Peer A et al (2017) Self-organized developmental patterning and differentiation in cerebral organoids. EMBO J 36:1316–1329. https://doi.org/10.15252/embj.201694700 · DOI · Paper page
  48. Sanchez Campos S, Alza NP, Salvador GA (2018) Lipid metabolism alterations in the neuronal response to A53T alpha-synuclein and Fe-induced injury. Arch Biochem Biophys 655:43–54. https://doi.org/10.1016/j.abb.2018.08.007 · DOI
  49. Schroder J, Lullmann-Rauch R, Himmerkus N, Pleines I, Nieswandt B, Orinska Z et al (2009) Deficiency of the tetraspanin CD63 associated with kidney pathology but normal lysosomal function. Mol Cell Biol 29:1083–1094. https://doi.org/10.1128/MCB.01163-08 · DOI
  50. Sidransky E, Lopez G (2012) The link between the GBA gene and parkinsonism. Lancet Neurol 11:986–998. https://doi.org/10.1016/S1474-4422(12)70190-4 · DOI
  51. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840. https://doi.org/10.1038/42166 · DOI · Paper page
  52. Suzuki M, Sango K, Wada K, Nagai Y (2018) Pathological role of lipid interaction with alpha-synuclein in Parkinson’s disease. Neurochem Int 119:97–106. https://doi.org/10.1016/j.neuint.2017.12.014 · DOI
  53. Trojanowski JQ, Lee VM (1998) Aggregation of neurofilament and alpha-synuclein proteins in Lewy bodies: implications for the pathogenesis of Parkinson disease and Lewy body dementia. Arch Neurol 55:151–152. https://doi.org/10.1001/archneur.55.2.151 · DOI
  54. Tsuang D, Leverenz JB, Lopez OL, Hamilton RL, Bennett DA, Schneider JA et al (2013) APOE epsilon4 increases risk for dementia in pure synucleinopathies. JAMA Neurol 70:223–228. https://doi.org/10.1001/jamaneurol.2013.600 · DOI · Paper page
  55. Wang M, Han X (2014) Multidimensional mass spectrometry-based shotgun lipidomics. Methods Mol Biol 1198:203–220. https://doi.org/10.1007/978-1-4939-1258-2_13 · DOI
  56. Wang M, Wang C, Han RH, Han X (2016) Novel advances in shotgun lipidomics for biology and medicine. Prog Lipid Res 61:83–108. https://doi.org/10.1016/j.plipres.2015.12.002 · DOI
  57. Woodard CM, Campos BA, Kuo SH, Nirenberg MJ, Nestor MW, Zimmer M et al (2014) iPSC-derived dopamine neurons reveal differences between monozygotic twins discordant for Parkinson’s disease. Cell Rep 9:1173–1182. https://doi.org/10.1016/j.celrep.2014.10.023 · DOI
  58. Wren MC, Zhao J, Liu CC, Murray ME, Atagi Y, Davis MD et al (2015) Frontotemporal dementia-associated N279K tau mutant disrupts subcellular vesicle trafficking and induces cellular stress in iPSC-derived neural stem cells. Mol Neurodegener 10:46. https://doi.org/10.1186/s13024-015-0042-7 · DOI
  59. Yamazaki Y, Liu CC, Yamazaki A, Shue F, Martens YA, Chen Y et al (2020) Vascular ApoE4 impairs behavior by modulating gliovascular function. Neuron. https://doi.org/10.1016/j.neuron.2020.11.019 · DOI · Paper page
  60. Yang K, Cheng H, Gross RW, Han X (2009) Automated lipid identification and quantification by multidimensional mass spectrometry-based shotgun lipidomics. Anal Chem 81:4356–4368. https://doi.org/10.1021/ac900241u · DOI
  61. Zhang Y, Sloan SA, Clarke LE, Caneda C, Plaza CA, Blumenthal PD et al (2016) Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron 89:37–53. https://doi.org/10.1016/j.neuron.2015.11.013 · DOI · Paper page
  62. Zhao J, Fu Y, Yamazaki Y, Ren Y, Davis MD, Liu CC et al (2020) APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer’s disease patient iPSC-derived cerebral organoids. Nat Commun 11:5540. https://doi.org/10.1038/s41467-020-19264-0 · DOI · Paper page
  63. Zhao N, Ren Y, Yamazaki Y, Qiao W, Li F, Felton LM et al (2020) Alzheimer’s risk factors age, APOE genotype, and sex drive distinct molecular pathways. Neuron 106(727–742):e726. https://doi.org/10.1016/j.neuron.2020.02.034 · DOI · Paper page

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Metadata

Authors
Zhao, J., Lu, W., Ren, Y., Fu, Y., Martens, Y. A., Shue, F., Davis, M. D., Wang, X., Chen, K., Li, F., Liu, C.-C., Graff-Radford, N. R., Wszolek, Z. K., Younkin, S. G., Brafman, D. A., Ertekin-Taner, N., Asmann, Y. W., Dickson, D. W., Xu, Z., Pan, M., Han, X., Kanekiyo, T., & Bu, G.
ORCID
Venue
Acta Neuropathologica
Publisher
Springer Science and Business Media LLC
Published
2021-08-28
Volume
142
Issue
5
Pages
807-825
ISSN
  • 0001-6322
  • 1432-0533
DOI
10.1007/s00401-021-02361-9
PMC
PMC8500881
Cited by
58
References
10
Language
en
Update notices
correction (2021-11-01)
Licence
Funders
  • National Institutes of Health (RF1AG051504, R37AG027924, RF1AG046205, RF1AG057181, P01NS074969, P30AG062677, R01AG061796, U19AG069701, U54NS110435, RF1AG068034, RF1AG071226)
  • Alzheimer's Association (2018-AARF-592302)

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