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Cited by 10Barrier Structure and Function StudiesAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

The influences of ApoE isoforms on endothelial adherens junctions and actin cytoskeleton responding to mCRP.

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Zhang, Zhengrong, Lin, Weiwei, Gan, Qini, Lei, Maohua, Gong, Bin, Zhang, Chao, Henrique, Jessica Salles, Han, Jingyan +6 more·2024·Angiogenesis
DOI 10.1007/s10456-024-09946-4PMC PMC11564276
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Abstract

Apolipoprotein E4 (ApoE4) plays an important role responding to monomeric C-reactive protein (mCRP) via binding to CD31 leading to cerebrovascular damage and Alzheimer's disease (AD). Using phosphor-proteomic profiling, we found altered cytoskeleton proteins in the microvasculature of AD brains, including increased levels of hyperphosphorylated tau (pTau) and the actin-related protein, LIMA1. To address the hypothesis that cytoskeletal changes serve as early pathological signatures linked with CD31 in brain endothelia in ApoE4 carriers, ApoE4 knock-in mice intraperitoneal injected with mCRP revealed that mCRP increased the expressions of phosphorylated CD31 (pCD31) and LIMA1, and facilitate the binding of pCD31 to LIMA1. mCRP combined with recombinant APOE4 protein decreased interaction of CD31 and VE-Cadherin at adherens junctions (AJs), along with altered the expression of various actin cytoskeleton proteins, causing microvasculature damage. Notably, the APOE2 protein attenuated these changes. Overall, our study demonstrates that ApoE4 responds to mCRP to disrupt the endothelial AJs which link with the actin cytoskeleton and this pathway could play a key role in the barrier dysfunction leading to AD risk.

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  • APOE isoforms differentially modulate components of cadherin-catenin complexes.

    “Cadherin signaling has also been linked to synaptic adhesion stability and neurodegeneration (Ando et al., 2011; Arikkath and Reichardt, 2008; Laszlo and Lele, 2022; Mysore et al., 2008), and APOE isoforms differentially modulate components of cadherin–catenin complexes (Ahmad et al., 2020; Zhang et al., 2024).”

    From Isogenic human stem cell models reveal mutation-dependent protective mechanisms of APOE3 Christchurch (2026) · cites this paper as Zhang et al., 2024

    The Results section on VE-cadherin reports that mCRP significantly reduced VE-cadherin–CD31 colocalization in ApoE4 mice, but not significantly in the other ApoE groups. This supports an isoform-dependent effect on an endothelial cadherin-associated junction under mCRP exposure; the passages do not establish modulation of catenin components or cadherin–catenin complexes generally. Page numbers were not available in our copy. (LLM, conf=0.86)

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Research works printed but not linked: 64

  1. [1]Iadecola C, Gottesman RF (2018) Cerebrovascular alterations in Alzheimer disease. Circ Res 123(4):406–408 30355253 PMC6214471
  2. [2]Garcia FJ, Sun N, Lee H, Godlewski B, Mathys H, Galani K, Zhou B, Jiang X, Ng AP, Mantero J, Tsai LH, Bennett DA, Sahin M, Kellis M, Heiman M (2022) Single-cell dissection of the human brain vasculature. Nature 603(7903):893–899 35158371 PMC9680899
  3. [3]Murdock MH, Tsai LH (2023) Insights into Alzheimer’s disease from single-cell genomic approaches. Nat Neurosci 26(2):181–195 36593328 PMC10155598
  4. [4]Bryant A, Li Z, Jayakumar R, Serrano-Pozo A, Woost B, Hu M, Woodbury ME, Wachter A, Lin G, Kwon T, Talanian RV, Biber K, Karran EH, Hyman BT, Das S, Bennett RE (2023) Endothelial cells are heterogeneous in different brain regions and are dramatically altered in Alzheimer’s disease. J Neurosci 43(24):4541–4557 37208174 PMC10278684
  5. [5]Cao W, Zheng H (2018) Peripheral immune system in aging and Alzheimer’s disease. Mol Neurodegener 13(1):51 30285785 PMC6169078
  6. [6]Zhang Z, Gan Q, Han J, Tao Q, Qiu WQ, Madri JA (2023) CD31 as a probable responding and gate-keeping protein of the blood-brain barrier and the risk of Alzheimer’s disease. J Cereb Blood Flow Metab. 10.1177/0271678X231170041 37051650 PMC10291450 · DOI
  7. [8]Zhang Z, Na H, Gan Q, Tao Q, Alekseyev Y, Hu J, Yan Z, Yang JB, Tian H, Zhu S, Li Q, Rajab IM, Blusztajn JK, Wolozin B, Emili A, Zhang X, Stein T, Potempa LA, Qiu WQ (2021) Monomeric C-reactive protein via endothelial CD31 for neurovascular inflammation in an ApoE genotype-dependent pattern: a risk factor for Alzheimer’s disease? Aging Cell. 10.1111/acel.13501 34687487 PMC8590103 · DOI · Paper page
  8. [9]Zhang H, Fan J, Zhao Z, Wang C, Wan LQ (2021) Effects of Alzheimer’s disease-related proteins on the chirality of brain endothelial cells. Cell Mol Bioeng 14(3):231–240 34109002 PMC8175509
  9. [10]Stamatovic SM, Johnson AM, Keep RF, Andjelkovic AV (2016) Junctional proteins of the blood-brain barrier: new insights into function and dysfunction. Tissue Barriers 4(1):e1154641 27141427 PMC4836471
  10. [11]Komarova YA, Kruse K, Mehta D, Malik AB (2017) Protein interactions at endothelial junctions and signaling mechanisms regulating endothelial permeability. Circ Res 120(1):179–206 28057793 PMC5225667
  11. [12]Privratsky JR, Newman PJ (2014) PECAM-1: regulator of endothelial junctional integrity. Cell Tissue Res 355(3):607–619 24435645 PMC3975704
  12. [13]Bodakuntla S, Jijumon AS, Villablanca C, Gonzalez-Billault C, Janke C (2019) Microtubule-associated proteins: structuring the cytoskeleton. Trends Cell Biol 29(10):804–819 31416684
  13. [14]Letort G, Ennomani H, Gressin L, Théry M, Blanchoin L (2015) Dynamic reorganization of the actin cytoskeleton. F1000Res. 10.12688/f1000research.6374.1 26989473 PMC4784019 · DOI
  14. [15]Shi Y, Zhang L, Pu H, Mao L, Hu X, Jiang X, Xu N, Stetler RA, Zhang F, Liu X, Leak RK, Keep RF, Ji X, Chen J (2016) Rapid endothelial cytoskeletal reorganization enables early blood-brain barrier disruption and long-term ischaemic reperfusion brain injury. Nat Commun 7:10523 26813496 PMC4737895
  15. [16]Taha M, Aldirawi M, März S, Seebach J, Odenthal-Schnittler M, Bondareva O, Bojovic V, Schmandra T, Wirth B, Mietkowska M, Rottner K, Schnittler H (2019) EPLIN-α and -β isoforms modulate endothelial cell dynamics through a spatiotemporally differentiated interaction with actin. Cell Rep 29(4):1010-1026.e6 31644899
  16. [17]Caprio V, Badimon L, Di Napoli M, Fang WH, Ferris GR, Guo B, Iemma RS, Liu D, Zeinolabediny Y, Slevin M (2018) pCRP-mCRP dissociation mechanisms as potential targets for the development of small-molecule anti-inflammatory chemotherapeutics. Front Immunol 9:1089 29892284 PMC5985513
  17. [18]Potempa LA, Yao ZY, Ji SR, Filep JG, Wu Y (2015) Solubilization and purification of recombinant modified C-reactive protein from inclusion bodies using reversible anhydride modification. Biophysics reports 1:18–33 26942216 PMC4762138
  18. [19]Nakayama S, Du Clos TW, Gewurz H, Mold C (1984) Inhibition of antibody responses to phosphocholine by C-reactive protein. J Immunol 132(3):1336–1340 6363539
  19. [20]Lee YK, Uchida H, Smith H, Ito A, Sanchez T (2019) The isolation and molecular characterization of cerebral microvessels. Nat Protoc 14(11):3059–3081 31586162 PMC11571963
  20. [22]Blum BC, Emili A (2021) Omics Notebook: robust, reproducible and flexible automated multiomics exploratory analysis and reporting. Bioinform Adv. 10.1093/bioadv/vbab024 36700091 PMC9710639 · DOI
  21. [24]Korotkevich EI, Rudik AV, Dmitriev AV, Lagunin AA, Filimonov DA (2021) Predict of metabolic stability of xenobiotics by the PASS and GUSAR programs. Biomed Khim 67(3):295–299 34142537
  22. [25]Subramanian A, Kuehn H, Gould J, Tamayo P, Mesirov JP (2007) GSEA-P: a desktop application for gene set enrichment analysis. Bioinformatics 23(23):3251–3253 17644558
  23. [26]Yousef H, Czupalla CJ, Lee D, Butcher EC, Wyss-Coray T (2018) Papain-based single cell isolation of primary murine brain endothelial cells using flow cytometry. Bio Protoc. 10.21769/BioProtoc.3091 31032379 PMC6482965 · DOI
  24. [27]Ying SC, Gewurz H, Kinoshita CM, Potempa LA, Siegel JN (1989) Identification and partial characterization of multiple native and neoantigenic epitopes of human C-reactive protein by using monoclonal antibodies. J Immunol 143(1):221–228 2471736
  25. [28]Zieba A, Ponten F, Uhlén M, Landegren U (2018) In situ protein detection with enhanced specificity using DNA-conjugated antibodies and proximity ligation. Mod Pathol 31(2):253–263 28937142
  26. [29]Hansson O, Blennow K, Zetterberg H, Dage J (2023) Blood biomarkers for Alzheimer’s disease in clinical practice and trials. Nat Aging 3(5):506–519 37202517 PMC10979350
  27. [30]Meydani M (2001) Nutrition interventions in aging and age-associated disease. Ann N Y Acad Sci 928:226–235 11795514
  28. [31]Laboy Cintron D, Muir AM, Scott A, McDonald M, Monaghan KG, Santiago-Sim T, Wentzensen IM, De Luca C, Brancati F, Harris DJ, Goueli C, Stottmann R, Prada CE, Biderman Waberski M, Mefford HC (2022) A recurrent, de novo pathogenic variant in ARPC4 disrupts actin filament formation and causes microcephaly and speech delay. HGG Adv 3(1):100072 35047857 PMC8756495
  29. [32]G. Sa, Z. Liu, J. Ren, Q. Wan, X. Xiong, Z. Yu, H. Chen, Y. Zhao, S. He, [Not Available], Cell. Signal. 61 (2019) 39-47 31082464
  30. [33]Illescas M, Peñas A, Arenas J, Martín MA, Ugalde C (2021) Regulation of mitochondrial function by the actin cytoskeleton. Front Cell Dev Biol 9:795838 34993202 PMC8725978
  31. [34]García-Caballero M, Zecchin A, Souffreau J, Truong AK, Teuwen LA, Vermaelen W, Martín-Pérez R, de Zeeuw P, Bouché A, Vinckier S, Cornelissen I, Eelen G, Ghesquière B, Mazzone M, Dewerchin M, Carmeliet P (2019) Role and therapeutic potential of dietary ketone bodies in lymph vessel growth. Nat Metab 1(7):666–675 32694649
  32. [35]Gnaiger E (2009) Capacity of oxidative phosphorylation in human skeletal muscle: new perspectives of mitochondrial physiology. Int J Biochem Cell Biol 41(10):1837–1845 19467914
  33. [36]Sluysmans S, Vasileva E, Spadaro D, Shah J, Rouaud F, Citi S (2017) The role of apical cell-cell junctions and associated cytoskeleton in mechanotransduction. Biol Cell 109(4):139–161 28220498
  34. [37]Schnoor M (2015) Endothelial actin-binding proteins and actin dynamics in leukocyte transendothelial migration. J Immunol 194(8):3535–3541 25848070
  35. [38]Sluiter TJ, van Buul JD, Huveneers S, Quax PHA, de Vries MR (2021) Endothelial barrier function and leukocyte transmigration in atherosclerosis. Biomedicines 9(4):328 33804952 PMC8063931
  36. [39]Gulino-Debrac D (2013) Mechanotransduction at the basis of endothelial barrier function. Tissue Barriers 1(2):e24180 24665386 PMC3879236
  37. [40]Givens C, Tzima E (2016) Endothelial mechanosignaling: does one sensor fit all? Antioxid Redox Signal 25(7):373–388 27027326 PMC5011625
  38. [41]Duong CN, Vestweber D (2020) Mechanisms ensuring endothelial junction integrity beyond VE-cadherin. Front Physiol 11:519 32670077 PMC7326147
  39. [42]Tzima E, Irani-Tehrani M, Kiosses WB, Dejana E, Schultz DA, Engelhardt B, Cao G, DeLisser H, Schwartz MA (2005) A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. Nature 437(7057):426–431 16163360
  40. [43]García-Ponce A, Citalán-Madrid AF, Velázquez-Avila M, Vargas-Robles H, Schnoor M (2015) The role of actin-binding proteins in the control of endothelial barrier integrity. Thromb Haemost 113(1):20–36 25183310
  41. [44]Woollard KJ, Phillips DC, Griffiths HR (2002) Direct modulatory effect of C-reactive protein on primary human monocyte adhesion to human endothelial cells. Clin Exp Immunol 130(2):256–262 12390313 PMC1906519
  42. [45]Na H, Yang JB, Zhang Z, Gan Q, Tian H, Rajab IM, Potempa LA, Tao Q, Qiu WQ (2023) Peripheral apolipoprotein E proteins and their binding to LRP1 antagonize Alzheimer’s disease pathogenesis in the brain during peripheral chronic inflammation. Neurobiol Aging 127:54–69 37060729 PMC10198819
  43. [46]Yadav T, Gau D, Roy P (2022) Mitochondria-actin cytoskeleton crosstalk in cell migration. J Cell Physiol 237(5):2387–2403 35342955 PMC9945482
  44. [47]Zhang YY, Fu ZY, Wei J, Qi W, Baituola G, Luo J, Meng YJ, Guo SY, Yin H, Jiang SY, Li YF, Miao HH, Liu Y, Wang Y, Li BL, Ma YT, Song BL (2018) A LIMA1 variant promotes low plasma LDL cholesterol and decreases intestinal cholesterol absorption. Science 360(6393):1087–1092 29880681
  45. [48]Mares J, Costa AP, Dartora WJ, Wartchow KM, Lazarian A, Bennett DA, Nuriel T, Menon V, McIntire LBJ (2024) Brain and serum lipidomic profiles implicate lands cycle acyl chain remodeling association with APOEε4 and mild cognitive impairment. Front Aging Neurosci 16:1419253 38938596 PMC11210445
  46. [49]Lampugnani MG (2010) Endothelial adherens junctions and the actin cytoskeleton: an ‘infinity net’? J Biol 9(3):16 20377920 PMC2871513
  47. [50]Gustafson S, Vessby B, Ostlund-Lindqvist AM (1988) Apolipoprotein-E-binding proteins of rat liver endothelial cells. Biochim Biophys Acta 962(1):73–80 3416008
  48. [51]Hsu BY, Bae YH, Mui KL, Liu SL, Assoian RK (2015) Apolipoprotein E3 inhibits Rho to regulate the mechanosensitive expression of Cox2. PLoS ONE 10(6):e0128974 26068461 PMC4465925
  49. [52]Marottoli FM, Zhang H, Flores-Barrera E, de la Villarmois EA, Damen FC, Miguelez Fernández AMM, Blesson HV, Chaudhary R, Nguyen AL, Nwokeji AE, Talati R, John AS, Madadakere K, Lutz SE, Cai K, Tseng KY, Tai LM (2023) Endothelial cell APOE3 regulates neurovascular, neuronal, and behavioral function. Arterioscler Thromb Vasc Biol. 10.1161/ATVBAHA.123.319816 37650329 PMC10521805 · DOI
  50. [53]Suica VI, Uyy E, Boteanu RM, Ivan L, Antohe F (2015) Alteration of actin dependent signaling pathways associated with membrane microdomains in hyperlipidemia. Proteome Sci 13:30 26628893 PMC4666118
  51. [54]Hoglund Z, Ruiz-Uribe N, Del Sastre E, Woost B, Bader E, Bailey J, Hyman BT, Zwang T, Bennett RE (2024) Brain vasculature accumulates tau and is spatially related to tau tangle pathology in Alzheimer’s disease. Acta Neuropathol 147(1):101 38884806 PMC11182845
  52. [55]Cross D, Vial C, Maccioni RB (1993) A tau-like protein interacts with stress fibers and microtubules in human and rodent cultured cell lines. J Cell Sci 105(Pt 1):51–60 7689576
  53. [56]DiTella M, Feiguin F, Morfini G, Cáceres A (1994) Microfilament-associated growth cone component depends upon Tau for its intracellular localization. Cell Motil Cytoskeleton 29(2):117–130 7820862
  54. [57]Kempf M, Clement A, Faissner A, Lee G, Brandt R (1996) Tau binds to the distal axon early in development of polarity in a microtubule- and microfilament-dependent manner. J Neurosci 16(18):5583–5592 8795614 PMC6578978
  55. [58]Simpson JE, Ince PG, Shaw PJ, Heath PR, Raman R, Garwood CJ, Gelsthorpe C, Baxter L, Forster G, Matthews FE, Brayne C, Wharton SB (2011) Microarray analysis of the astrocyte transcriptome in the aging brain: relationship to Alzheimer’s pathology and APOE genotype. Neurobiol Aging 32(10):1795–1807 21705112
  56. [59]Huang J, Stein TD, Wang Y, Ang TFA, Tao Q, Lunetta KL, Massaro J, Akhter-Khan SC, Mez J, Au R, Farrer LA, Zhang X, Qiu WQ (2023) Blood levels of MCP-1 modulate the genetic risks of Alzheimer’s disease mediated by HLA-DRB1 and APOE for Alzheimer’s disease. Alzheimers Dement 19(5):1925–1937 36396603 PMC10182187
  57. [60]Merched A, Serot JM, Visvikis S, Aguillon D, Faure G, Siest G (1998) Apolipoprotein E, transthyretin and actin in the CSF of Alzheimer’s patients: relation with the senile plaques and cytoskeleton biochemistry. FEBS Lett 425(2):225–228 9559653
  58. [61]Ray M, Zhang W (2010) Analysis of Alzheimer’s disease severity across brain regions by topological analysis of gene co-expression networks. BMC Syst Biol 4:136 20925940 PMC2976747
  59. [62]You Y, Muraoka S, Jedrychowski MP, Hu J, McQuade AK, Young-Pearse T, Aslebagh R, Shaffer SA, Gygi SP, Blurton-Jones M, Poon WW, Ikezu T (2022) Human neural cell type-specific extracellular vesicle proteome defines disease-related molecules associated with activated astrocytes in Alzheimer’s disease brain. J Extracell Vesicles 11(1):e12183 35029059 PMC8758831
  60. [63]Balczon R, Pittet JF, Wagener BM, Moser SA, Voth S, Vorhees CV, Williams MT, Bridges JP, Alvarez DF, Koloteva A, Xu Y, Zha XM, Audia JP, Stevens T, Lin MT (2019) Infection-induced endothelial amyloids impair memory. FASEB J 33(9):10300–10314 31211919 PMC6704457
  61. [64]Melková K, Zapletal V, Narasimhan S, Jansen S, Hritz J, Škrabana R, Zweckstetter M, Ringkjøbing Jensen M, Blackledge M, Žídek L (2019) Structure and functions of microtubule associated proteins Tau and MAP2c: similarities and differences. Biomolecules 9(3):105 30884818 PMC6468450
  62. [65]Fulga TA, Elson-Schwab I, Khurana V, Steinhilb ML, Spires TL, Hyman BT, Feany MB (2007) Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo. Nat Cell Biol 9(2):139–148 17187063
  63. [66]Dogterom M, Koenderink GH (2019) Actin-microtubule crosstalk in cell biology. Nat Rev Mol Cell Biol 20(1):38–54 30323238
  64. [67]Kirst C, Skriabine S, Vieites-Prado A, Topilko T, Bertin P, Gerschenfeld G, Verny F, Topilko P, Michalski N, Tessier-Lavigne M, Renier N (2020) Mapping the fine-scale organization and plasticity of the brain vasculature. Cell 180(4):780-795.e25 32059781

Cited by

Sorted by citations

Authors
Zhang, Z., Lin, W., Gan, Q., Lei, M., Gong, B., Zhang, C., Henrique, J. S., Han, J., Tian, H., Tao, Q., Potempa, L. A., Stein, T. D., Emili, A., & Qiu, W. Q.
Affiliations
  • Boston University (US)
  • The University of Texas Medical Branch at Galveston (US)
  • Roosevelt University (US)
Corresponding author
  • Stein, Thor D.
  • Emili, Andrew
  • Qiu, Wei Qiao
ORCID
Venue
Angiogenesis
Publisher
Springer Science and Business Media LLC
Published
2024-09-14
Volume
27
Issue
4
Pages
861-881
ISSN
  • 0969-6970 (ISSN-L)
  • 1573-7209
DOI
10.1007/s10456-024-09946-4
PMC
PMC11564276
OpenAlex
W4402538358
Cited by
10
References
3
Citations by year
2026: 4 · 2025: 6
FWCI
1.46
Type
journal article
Language
en
Open access
Licence
Locations
  • Angiogenesis (publishedVersion, cc-by-nc-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
National Institute on Aging (R01 AG054546)
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
apolipoprotein E isoforms, APOE ε4, APOE2, monomeric C-reactive protein, CD31, VE-cadherin, adherens junctions, actin cytoskeleton, LIMA1, hyperphosphorylated tau, cerebral microvasculature, blood-brain barrier dysfunction, Alzheimer's disease, cerebrovascular injury
MeSH terms
Alzheimer Disease, Animals, Apolipoproteins E, Brain, C-Reactive Protein, Female, Humans, Male, Mice, Transgenic, Actin Cytoskeleton, Cadherins, Platelet Endothelial Cell Adhesion Molecule-1, Protein Isoforms, Adherens Junctions, Endothelial Cells, Mice, Apolipoprotein E4

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