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Platelet Proteomic Analysis Revealed Differential Pattern of Cytoskeletal- and Immune-Related Proteins at Early Stages of Alzheimer’s Disease

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Abstract

Platelets are considered a good model system to study a number of elements associated with neuronal pathways as they share biochemical similarities. Platelets represent the major source of amyloid-β (Aβ) in blood contributing to the Aβ accumulation in the brain parenchyma and vasculature. Peripheral blood platelet alterations including cytoskeletal abnormalities, abnormal cytoplasmic calcium fluxes or increased oxidative stress levels have been related to Alzheimer’s disease (AD) pathology. Therefore, platelets can be considered a peripheral model to study metabolic mechanisms occurring in AD. To investigate peripheral molecular alterations, we examined platelet protein expression in a cohort of 164 subjects, including mild cognitive impairment (MCI), and AD patients, and healthy aged-matched controls. A two-dimensional difference gel electrophoresis (2D-DIGE) discovery phase revealed significant differences between patients and controls in five proteins: talin, vinculin, moesin, complement C3b and Rho GDP, which are known to be involved in cytoskeletal regulation including focal adhesions, inflammation and immune functions. Western blot analysis verified that talin was found to be increased in mild and moderate AD groups versus control, while the other three were found to be decreased. We also analysed amyloid precursor protein (APP), amyloid-β 1-40 (Aβ40) and 1-42 (Aβ42) levels in platelets from the same groups of subjects. Upregulation of platelet APP and Aβ peptides was found in AD patients compared to controls. These findings complement and expand previous reports concerning the morphological and functional alterations in AD platelets, and provide more insights into possible mechanisms that participate in the multifactorial and systemic damage in AD.

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  • 02 May 2020

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References

  1. Pellicano M, Bulati M, Buffa S, Barbagallo M, Di Prima A, Misiano G, Picone P, Di Carlo M et al (2010) Systemic immune responses in Alzheimer's disease: in vitro mononuclear cell activation and cytokine production. J Alzheimers Dis 21(1):181–192. https://doi.org/10.3233/jad-2010-091714

    Article  CAS  PubMed  Google Scholar 

  2. Zhang R, Miller RG, Madison C, Jin X, Honrada R, Harris W, Katz J, Forshew DA et al (2013) Systemic immune system alterations in early stages of Alzheimer’s disease. J Neuroimmunol 256(1–2):38–42. https://doi.org/10.1016/j.jneuroim.2013.01.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Takeda S, Sato N, Morishita R (2014) Systemic inflammation, blood-brain barrier vulnerability and cognitive/non-cognitive symptoms in Alzheimer disease: relevance to pathogenesis and therapy. Front Aging Neurosci 6:171. https://doi.org/10.3389/fnagi.2014.00171

    Article  PubMed  PubMed Central  Google Scholar 

  4. Bartolome F, de Las Cuevas N, Munoz U, Bermejo F, Martin-Requero A (2007) Impaired apoptosis in lymphoblasts from Alzheimer's disease patients: cross-talk of Ca2+/calmodulin and ERK1/2 signaling pathways. Cell Mol Life Sci : CMLS 64(11):1437–1448. https://doi.org/10.1007/s00018-007-7081-3

    Article  CAS  PubMed  Google Scholar 

  5. Nurden AT (2011) Platelets, inflammation and tissue regeneration. Thromb Haemost 105(Suppl 1):S13–S33. https://doi.org/10.1160/ths10-11-0720

    Article  CAS  PubMed  Google Scholar 

  6. Catricala S, Torti M, Ricevuti G (2012) Alzheimer disease and platelets: how’s that relevant. Immunity & ageing : I & A 9(1):20. https://doi.org/10.1186/1742-4933-9-20

    Article  CAS  Google Scholar 

  7. Vignini A, Nanetti L, Moroni C, Tanase L, Bartolini M, Luzzi S, Provinciali L, Mazzanti L (2007) Modifications of platelet from Alzheimer disease patients: a possible relation between membrane properties and NO metabolites. Neurobiol Aging 28(7):987–994. https://doi.org/10.1016/j.neurobiolaging.2006.05.010

    Article  CAS  PubMed  Google Scholar 

  8. Bush AI, Martins RN, Rumble B, Moir R, Fuller S, Milward E, Currie J, Ames D et al (1990) The amyloid precursor protein of Alzheimer’s disease is released by human platelets. J Biol Chem 265(26):15977–15983

    CAS  PubMed  Google Scholar 

  9. Smirnov A, Trupp A, Henkel AW, Bloch E, Reulbach U, Lewczuk P, Riggert J, Kornhuber J et al (2009) Differential processing and secretion of Abeta peptides and sAPPalpha in human platelets is regulated by thrombin and prostaglandine 2. Neurobiol Aging 30(10):1552–1562. https://doi.org/10.1016/j.neurobiolaging.2007.12.009

    Article  CAS  PubMed  Google Scholar 

  10. Colciaghi F, Marcello E, Borroni B, Zimmermann M, Caltagirone C, Cattabeni F, Padovani A, Di Luca M (2004) Platelet APP, ADAM 10 and BACE alterations in the early stages of Alzheimer disease. Neurology 62(3):498–501

    Article  CAS  Google Scholar 

  11. Chen M, Inestrosa NC, Ross GS, Fernandez HL (1995) Platelets are the primary source of amyloid beta-peptide in human blood. Biochem Biophys Res Commun 213(1):96–103. https://doi.org/10.1006/bbrc.1995.2103

    Article  CAS  PubMed  Google Scholar 

  12. Davies TA, Long HJ, Sgro K, Rathbun WH, McMenamin ME, Seetoo K, Tibbles H, Billingslea AM et al (1997) Activated Alzheimer disease platelets retain more beta amyloid precursor protein. Neurobiol Aging 18(2):147–153

    Article  CAS  Google Scholar 

  13. Gowert NS, Donner L, Chatterjee M, Eisele YS, Towhid ST, Munzer P, Walker B, Ogorek I et al (2014) Blood platelets in the progression of Alzheimer’s disease. PLoS One 9(2):e90523. https://doi.org/10.1371/journal.pone.0090523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Davies TA, Long HJ, Eisenhauer PB, Hastey R, Cribbs DH, Fine RE, Simons ER (2000) Beta amyloid fragments derived from activated platelets deposit in cerebrovascular endothelium: usage of a novel blood brain barrier endothelial cell model system. Amyloid : Int J Exp Clin Investig : Off J Int Soc Amyloidosis 7(3):153–165

    Article  CAS  Google Scholar 

  15. Kawamoto EM, Munhoz CD, Glezer I, Bahia VS, Caramelli P, Nitrini R, Gorjao R, Curi R et al (2005) Oxidative state in platelets and erythrocytes in aging and Alzheimer's disease. Neurobiol Aging 26(6):857–864. https://doi.org/10.1016/j.neurobiolaging.2004.08.011

    Article  CAS  PubMed  Google Scholar 

  16. Evin G, Zhu A, Holsinger RM, Masters CL, Li QX (2003) Proteolytic processing of the Alzheimer’s disease amyloid precursor protein in brain and platelets. J Neurosci Res 74(3):386–392. https://doi.org/10.1002/jnr.10745

    Article  CAS  PubMed  Google Scholar 

  17. Tang K, Hynan LS, Baskin F, Rosenberg RN (2006) Platelet amyloid precursor protein processing: a bio-marker for Alzheimer’s disease. J Neurol Sci 240(1–2):53–58. https://doi.org/10.1016/j.jns.2005.09.002

    Article  CAS  PubMed  Google Scholar 

  18. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, Klunk WE, Koroshetz WJ et al (2011) The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s & Dementia : J Alzheimer's Assoc 7(3):263–269. https://doi.org/10.1016/j.jalz.2011.03.005

    Article  Google Scholar 

  19. Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM et al (2011) The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s & Dementia : J Alzheimer’s Assoc 7(3):270–279. https://doi.org/10.1016/j.jalz.2011.03.008

    Article  Google Scholar 

  20. Morris JC (1993) The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 43(11):2412–2414

    Article  CAS  Google Scholar 

  21. Folstein MF, Folstein SE, McHugh PR (1975) “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12(3):189–198

    Article  CAS  Google Scholar 

  22. Krzyzanowska A, Garcia-Consuegra I, Pascual C, Antequera D, Ferrer I, Carro E (2015) Expression of regulatory proteins in choroid plexus changes in early stages of Alzheimer disease. J Neuropathol Exp Neurol 74(4):359–369. https://doi.org/10.1097/nen.0000000000000181

    Article  CAS  PubMed  Google Scholar 

  23. Roher AE, Esh CL, Kokjohn TA, Castano EM, Van Vickle GD, Kalback WM, Patton RL, Luehrs DC et al (2009) Amyloid beta peptides in human plasma and tissues and their significance for Alzheimer’s disease. Alzheimer's Dementia : J Alzheimer's Assoc 5(1):18–29. https://doi.org/10.1016/j.jalz.2008.10.004

    Article  CAS  Google Scholar 

  24. Gattaz WF, Talib LL, Schaeffer EL, Diniz BS, Forlenza OV (2014) Low platelet iPLA(2) activity predicts conversion from mild cognitive impairment to Alzheimer’s disease: a 4-year follow-up study. J Neural Transm (Vienna) 121(2):193–200. https://doi.org/10.1007/s00702-013-1088-8

    Article  CAS  Google Scholar 

  25. Torres AJ, Vasudevan L, Holowka D, Baird BA (2008) Focal adhesion proteins connect IgE receptors to the cytoskeleton as revealed by micropatterned ligand arrays. Proc Natl Acad Sci U S A 105(45):17238–17244. https://doi.org/10.1073/pnas.0802138105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ziegler WH, Gingras AR, Critchley DR, Emsley J (2008) Integrin connections to the cytoskeleton through talin and vinculin. Biochem Soc Trans 36(Pt 2):235–239. https://doi.org/10.1042/bst0360235

    Article  CAS  PubMed  Google Scholar 

  27. Goldmann WH, Auernheimer V, Thievessen I, Fabry B (2013) Vinculin, cell mechanics and tumour cell invasion. Cell Biol Int 37(5):397–405. https://doi.org/10.1002/cbin.10064

    Article  CAS  PubMed  Google Scholar 

  28. Ellis SJ, Goult BT, Fairchild MJ, Harris NJ, Long J, Lobo P, Czerniecki S, Van Petegem F et al (2013) Talin autoinhibition is required for morphogenesis. Curr Biol : CB 23(18):1825–1833. https://doi.org/10.1016/j.cub.2013.07.054

    Article  CAS  PubMed  Google Scholar 

  29. Sonkar VK, Kulkarni PP, Dash D (2014) Amyloid beta peptide stimulates platelet activation through RhoA-dependent modulation of actomyosin organization. FASEB J: Off Publ Fed Am Soc Exp Biol 28(4):1819–1829. https://doi.org/10.1096/fj.13-243691

    Article  CAS  Google Scholar 

  30. Bonifati DM, Kishore U (2007) Role of complement in neurodegeneration and neuroinflammation. Mol Immunol 44(5):999–1010. https://doi.org/10.1016/j.molimm.2006.03.007

    Article  CAS  PubMed  Google Scholar 

  31. Carroll MC (2004) The complement system in regulation of adaptive immunity. Nat Immunol 5(10):981–986. https://doi.org/10.1038/ni1113

    Article  CAS  PubMed  Google Scholar 

  32. van Beek J, Elward K, Gasque P (2003) Activation of complement in the central nervous system: roles in neurodegeneration and neuroprotection. Ann N Y Acad Sci 992:56–71

    Article  Google Scholar 

  33. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P et al (2000) Inflammation and Alzheimer’s disease. Neurobiol Aging 21(3):383–421

    Article  CAS  Google Scholar 

  34. Akiyama H, McGeer PL (1990) Brain microglia constitutively express beta-2 integrins. J Neuroimmunol 30(1):81–93

    Article  CAS  Google Scholar 

  35. Eikelenboom P, Stam FC (1982) Immunoglobulins and complement factors in senile plaques. An immunoperoxidase study. Acta Neuropathol 57(2–3):239–242

    Article  CAS  Google Scholar 

  36. Strohmeyer R, Ramirez M, Cole GJ, Mueller K, Rogers J (2002) Association of factor H of the alternative pathway of complement with agrin and complement receptor 3 in the Alzheimer’s disease brain. J Neuroimmunol 131(1–2):135–146

    Article  CAS  Google Scholar 

  37. Rogers J, Li R, Mastroeni D, Grover A, Leonard B, Ahern G, Cao P, Kolody H et al (2006) Peripheral clearance of amyloid beta peptide by complement C3-dependent adherence to erythrocytes. Neurobiol Aging 27(12):1733–1739. https://doi.org/10.1016/j.neurobiolaging.2005.09.043

    Article  CAS  PubMed  Google Scholar 

  38. Marksteiner J, Humpel C (2013) Platelet-derived secreted amyloid-precursor protein-beta as a marker for diagnosing Alzheimer’s disease. Curr Neurovasc Res 10(4):297–303

    Article  CAS  Google Scholar 

  39. Vignini A, Morganti S, Salvolini E, Sartini D, Luzzi S, Fiorini R, Provinciali L, Di Primio R et al (2013) Amyloid precursor protein expression is enhanced in human platelets from subjects with Alzheimer’s disease and frontotemporal lobar degeneration: a real-time PCR study. Exp Gerontol 48:1505–1508. https://doi.org/10.1016/j.exger.2013.10.008

    Article  CAS  PubMed  Google Scholar 

  40. Cupello A, Favale E, Audenino D, Scarrone S, Gastaldi S, Albano C (2005) Decrease of serotonin transporters in blood platelets after epileptic seizures. Neurochem Res 30(4):425–428

    Article  CAS  Google Scholar 

  41. Rainesalo S, Keranen T, Saransaari P, Honkaniemi J (2005) GABA and glutamate transporters are expressed in human platelets. Brain Res Mol Brain Res 141(2):161–165. https://doi.org/10.1016/j.molbrainres.2005.08.013

    Article  CAS  PubMed  Google Scholar 

  42. Rosenberg RN, Baskin F, Fosmire JA, Risser R, Adams P, Svetlik D, Honig LS, Cullum CM et al (1997) Altered amyloid protein processing in platelets of patients with Alzheimer disease. Arch Neurol 54(2):139–144

    Article  CAS  Google Scholar 

  43. Baskin F, Rosenberg RN, Iyer L, Hynan L, Cullum CM (2000) Platelet APP isoform ratios correlate with declining cognition in AD. Neurology 54(10):1907–1909

    Article  CAS  Google Scholar 

  44. Abraham CR, Marshall DC, Tibbles HE, Otto K, Long HJ, Billingslea AM, Hastey R, Johnson R et al (1999) Platelets and DAMI megakaryocytes possess beta-secretase-like activity. J Lab Clin Med 133(5):507–515

    Article  CAS  Google Scholar 

  45. Prodan CI, Szasz R, Vincent AS, Ross ED, Dale GL (2006) Coated-platelets retain amyloid precursor protein on their surface. Platelets 17(1):56–60. https://doi.org/10.1080/09537100500181913

    Article  CAS  PubMed  Google Scholar 

  46. Casoli T, Di Stefano G, Giorgetti B, Grossi Y, Balietti M, Fattoretti P, Bertoni-Freddari C (2007) Release of beta-amyloid from high-density platelets: implications for Alzheimer’s disease pathology. Ann N Y Acad Sci 1096:170–178. https://doi.org/10.1196/annals.1397.082

    Article  CAS  PubMed  Google Scholar 

  47. Casoli T, Di Stefano G, Giorgetti B, Balietti M, Recchioni R, Moroni F, Marcheselli F, Bernardini G et al (2008) Platelet as a physiological model to investigate apoptotic mechanisms in Alzheimer beta-amyloid peptide production. Mech Ageing Dev 129(3):154–162. https://doi.org/10.1016/j.mad.2007.11.004

    Article  CAS  PubMed  Google Scholar 

  48. Zhao S, Zhao J, Zhang T, Guo C (2016) Increased apoptosis in the platelets of patients with Alzheimer’s disease and amnestic mild cognitive impairment. Clin Neurol Neurosurg 143:46–50. https://doi.org/10.1016/j.clineuro.2016.02.015

    Article  PubMed  Google Scholar 

  49. Johnston JA, Liu WW, Coulson DT, Todd S, Murphy S, Brennan S, Foy CJ, Craig D et al (2008) Platelet beta-secretase activity is increased in Alzheimer’s disease. Neurobiol Aging 29(5):661–668. https://doi.org/10.1016/j.neurobiolaging.2006.11.003

    Article  CAS  PubMed  Google Scholar 

  50. McGuinness B, Fuchs M, Barrett SL, Passmore AP, Johnston JA (2016) Platelet membrane beta-secretase activity in mild cognitive impairment and conversion to dementia: a longitudinal study. J Alzheimer's Dis: JAD 49(4):1095–1103. https://doi.org/10.3233/jad-150795

    Article  CAS  Google Scholar 

  51. Donner L, Falker K, Gremer L, Klinker S, Pagani G, Ljungberg LU, Lothmann K, Rizzi F et al (2016) Platelets contribute to amyloid-beta aggregation in cerebral vessels through integrin alphaIIbbeta3-induced outside-in signaling and clusterin release. Sci Signal 9(429):ra52. https://doi.org/10.1126/scisignal.aaf6240

    Article  CAS  PubMed  Google Scholar 

  52. Olkkonen VM, Ikonen E (2006) When intracellular logistics fails—genetic defects in membrane trafficking. J Cell Sci 119(Pt 24):5031–5045. https://doi.org/10.1242/jcs.03303

    Article  CAS  PubMed  Google Scholar 

  53. Wang J, Ohno-Matsui K, Yoshida T, Kojima A, Shimada N, Nakahama K, Safranova O, Iwata N et al (2008) Altered function of factor I caused by amyloid beta: implication for pathogenesis of age-related macular degeneration from Drusen. J Immunol (Baltimore, Md : 1950) 181(1):712–720

    Article  CAS  Google Scholar 

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Acknowledgements

We are grateful to the patients and donors without which this work would not have been possible. We also thank the i+12 Proteomic Unit, in particular Ines Garcia-Consuegra for her advice in the proteomic analysis. We also thank Lola Gutierrez from the UCM CAI-Proteomic Unit helping to analyse and understand the 2D-DIGE results.

Funding

This study was supported by grants from the Instituto de Salud Carlos III (PI12/00486; CM15/00222; PI15/00780), FEDER, and CIBERNED.

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Authors and Affiliations

  1. Group of Neurodegenerative Diseases, Hospital 12 de Octubre Research Institute (imas12), 28041, Madrid, Spain

    Marta González-Sánchez, Teresa Díaz, Consuelo Pascual, Desiree Antequera, Alejandro Herrero-San Martín, Sara Llamas-Velasco, Alberto Villarejo-Galende, Fernando Bartolome & Eva Carro

  2. Biomedical Research Networking Center in Neurodegenerative Diseases (CIBERNED), Madrid, Spain

    Marta González-Sánchez, Desiree Antequera, Alejandro Herrero-San Martín, Sara Llamas-Velasco, Alberto Villarejo-Galende, Fernando Bartolome & Eva Carro

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  1. Marta González-Sánchez
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  2. Teresa Díaz
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Correspondence to Fernando Bartolome or Eva Carro.

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Blood samples were obtained through antecubital vein puncture. Donors gave written consent, in accordance with the Declaration of Helsinki and the project was approved by the local ethical review committee from the Research Institute Hospital 12 de Octubre (i+12).

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González-Sánchez, M., Díaz, T., Pascual, C. et al. Platelet Proteomic Analysis Revealed Differential Pattern of Cytoskeletal- and Immune-Related Proteins at Early Stages of Alzheimer’s Disease. Mol Neurobiol 55, 8815–8825 (2018). https://doi.org/10.1007/s12035-018-1039-3

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