Advertisement

Neurochemical Research

, Volume 44, Issue 6, pp 1375–1386 | Cite as

Platelets Bioenergetics Screening Reflects the Impact of Brain Aβ Plaque Accumulation in a Rat Model of Alzheimer

  • Federico A. Prestia
  • Pablo Galeano
  • Pamela V. Martino Adami
  • Sonia Do Carmo
  • Eduardo M. Castaño
  • A. Claudio Cuello
  • Laura MorelliEmail author
Original Paper

Abstract

Alzheimer’s disease (AD) is associated to depressed brain energy supply and impaired cortical and hippocampal synaptic function. It was previously reported in McGill-R-Thy1-APP transgenic (Tg(+/+)) rats that Aβ deposition per se is sufficient to cause abnormalities in glucose metabolism and neuronal connectivity. These data support the utility of this animal model as a platform for the search of novel AD biomarkers based on bioenergetic status. Recently, it has been proposed that energy dysfunction can be dynamically tested in platelets (PLTs) of nonhuman primates. PLTs are good candidates to find peripheral biomarkers for AD because they may reflect in periphery the bioenergetics deficits and the inflammatory and oxidative stress processes taking place in AD brain. In the present study, we carried out a PLTs bioenergetics screening in advanced-age (12–14 months old) control (WT) and Tg(+/+) rats. Results indicated that thrombin-activated PLTs of Tg(+/+) rats showed a significantly lower respiratory rate, as compared to that measured in WT animals, when challenged with the same dose of FCCP (an uncoupler of oxidative phosphorylation). In summary, our results provide original evidence that PLTs bioenergetic profiling may reflect brain bioenergetics dysfunction mediated by Aβ plaque accumulation. Further studies on human PLTs from control and AD patients are required to validate the usefulness of PLTs bioenergetics as a novel blood-based biomarker for AD.

Keywords

Alzheimer’s disease Brain dysfunction Platelet bioenergetic Transgenic rat Amyloid β Blood-based bioenergetic profiling 

Notes

Acknowledgements

We acknowledge the helpful assistance of the personnel of the Laboratory of Hospital Naval Cirujano Dr. Pedro Mallo (Ciudad de Buenos Aires-Argentina) on the determination of the haematologic indices in animals. We wish to thank Dr. Mirta Schattner and Dr. Roberto G. Pozner of the Laboratory of Experimental Thrombosis- Academia Nacional de Medicina (Ciudad de Buenos Aires-Argentina) for their support on the evaluation of platelet aggregation.

Funding

This study was supported by funding from the Agencia Nacional de Promoción Científica y Tecnológica (Grant Nos. PICT-2015-0285, PICT-2016-4647 and PIBT/09 2013 to LM; PICT-2013-318 to EMC), Consejo Nacional de Investigaciones Científicas y Técnicas (Grant No. PIP-0378 to LM), Canadian Institutes of Health Research (Grant Nos. 201603PJT-364544 to ACC). FAP is supported by FONCyT fellowship. PVMA is supported by CONICET fellowship. PG, EMC, and LM are members of the Research Career of CONICET. SDC is the holder of the Charles E. Frosst/Merck Research Associate position. ACC is member of the Canadian Consortium of Neurodegeneration in Aging (CCNA) and holder of the McGill University Charles E. Frosst/Merck Chair in Pharmacology.

Supplementary material

11064_2018_2657_MOESM1_ESM.pdf (210 kb)
Supplementary material 1 (PDF 210 KB)

References

  1. 1.
    Alzheimer’s Association (2013) Alzheimer’s disease facts and figures. Alzheimers Dement 9:208–245.  https://doi.org/10.1016/j.jalz.2013.02.003 CrossRefGoogle Scholar
  2. 2.
    Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356.  https://doi.org/10.1126/science.1072994 CrossRefGoogle Scholar
  3. 3.
    Aisen PS, Andrieu S, Sampaio C, Carrillo M, Khachaturian ZS, Dubois B, Feldman HH, Petersen RC, Siemers E, Doody RS, Hendrix SB, Grundman M, Schneider LS, Schindler RJ, Salmon E, Potter WZ, Thomas RG, Salmon D, Donohue M, Bednar MM, Touchon J, Vellas B (2011) Report of the task force on designing clinical trials in early (predementia) AD. Neurology 76:280–286.  https://doi.org/10.1212/WNL.0b013e318207b1b9 CrossRefGoogle Scholar
  4. 4.
    Zhang XL, Liu XJ, Hu SS, Thomas S, Tian YQ, Gao RL, Wu QY, Wei HX, Yang XB, Wang H, He ZX, Schelbert HR (2008) Impact of viable myocardium assessed by 99Tcm-MIBI SPECT and 18F-FDG PET imaging on clinical outcome of patients with left ventricular aneurysm underwent revascularization. Zhonghua Xin Xue Guan Bing Za Zhi 36:999–1003.  https://doi.org/10.3321/j.issn:0253-3758.2008.11.010 Google Scholar
  5. 5.
    Baird AL, Westwood S, Lovestone S (2015) Blood-based proteomic biomarkers of Alzheimer’s disease pathology. Front Neurol 6:236.  https://doi.org/10.3389/fneur.2015.00236 CrossRefGoogle Scholar
  6. 6.
    Pletscher A, Laubscher A (1980) Blood platelets as models for neurons: uses and limitations. J Neural Transm Suppl 16:7–16.  https://doi.org/10.1007/978-3-7091-8582-7_2 Google Scholar
  7. 7.
    Talib LL, Joaquim HP, Forlenza OV (2012) Platelet biomarkers in Alzheimer’s disease. World J Psychiatry 2:95–101.  https://doi.org/10.5498/wjp.v2.i6.95 CrossRefGoogle Scholar
  8. 8.
    Behari M, Shrivastava M (2013) Role of platelets in neurodegenerative diseases: a universal pathophysiology. Int J Neurosci 123:287–299.  https://doi.org/10.3109/00207454.2012.751534 CrossRefGoogle Scholar
  9. 9.
    Machlus KR, Thon JN, Italiano JE (2014) Interpreting the developmental dance of the megakaryocyte: a review of the cellular and molecular processes mediating platelet formation. Br J Haematol 165:227–236.  https://doi.org/10.1111/bjh.12758 CrossRefGoogle Scholar
  10. 10.
    Yun SH, Sim EH, Goh RY, Park JI, Han JY (2016) Platelet activation: the mechanisms and potential biomarkers. Biomed Res Int 2016:9060143.  https://doi.org/10.1155/2016/9060143 CrossRefGoogle Scholar
  11. 11.
    Jennings LK (2009) Mechanisms of platelet activation: need for new strategies to protect against platelet-mediated atherothrombosis. Thromb Haemost 102:248–257.  https://doi.org/10.1160/TH09-03-0192 CrossRefGoogle Scholar
  12. 12.
    Ponomarev ED (2018) Fresh evidence for platelets as neuronal and innate immune cells: their role in the activation, differentiation, and deactivation of Th1, Th17, and Tregs during tissue inflammation. Front Immunol 9:406.  https://doi.org/10.3389/fimmu.2018.00406 CrossRefGoogle Scholar
  13. 13.
    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 CrossRefGoogle Scholar
  14. 14.
    Catricala S, Torti M, Ricevuti G (2012) Alzheimer disease and platelets: how’s that relevant. Immun Ageing 9:20.  https://doi.org/10.1186/1742-4933-9-20 CrossRefGoogle Scholar
  15. 15.
    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 7:153–165.  https://doi.org/10.3109/13506120009146830 CrossRefGoogle Scholar
  16. 16.
    Di Luca M, Colciaghi F, Pastorino L, Borroni B, Padovani A, Cattabeni F (2000) Platelets as a peripheral district where to study pathogenetic mechanisms of alzheimer disease: the case of amyloid precursor protein. Eur J Pharmacol 405:277–283.  https://doi.org/10.1016/S0014-2999(00)00559-8 CrossRefGoogle Scholar
  17. 17.
    Tyrrell DJ, Bharadwaj MS, Jorgensen MJ, Register TC, Shively C, Andrews RN, Neth B, Keene CD, Mintz A, Craft S, Molina AJA (2017) Blood-based bioenergetic profiling reflects differences in brain bioenergetics and metabolism. Oxid Med Cell Longev 2017:7317251.  https://doi.org/10.1155/2017/7317251 CrossRefGoogle Scholar
  18. 18.
    Chacko BK, Kramer PA, Ravi S, Benavides GA, Mitchell T, Dranka BP, Ferrick D, Singal AK, Ballinger SW, Bailey SM, Hardy RW, Zhang J, Zhi D, Darley-Usmar VM (2014) The Bioenergetic Health Index: a new concept in mitochondrial translational research. Clin Sci (Lond) 127:367–373.  https://doi.org/10.1042/CS20140101 CrossRefGoogle Scholar
  19. 19.
    Gotz J, Ittner LM (2008) Animal models of Alzheimer’s disease and frontotemporal dementia. Nat Rev Neurosci 9:532–544.  https://doi.org/10.1038/nrn2420 CrossRefGoogle Scholar
  20. 20.
    Leon WC, Canneva F, Partridge V, Allard S, Ferretti MT, DeWilde A, Vercauteren F, Atifeh R, Ducatenzeiler A, Klein W, Szyf M, Alhonen L, Cuello AC (2010) A novel transgenic rat model with a full Alzheimer’s-like amyloid pathology displays pre-plaque intracellular amyloid-beta-associated cognitive impairment. J Alzheimers Dis 20:113–126.  https://doi.org/10.3233/JAD-2010-1349 CrossRefGoogle Scholar
  21. 21.
    Parent MJ, Zimmer ER, Shin M, Kang MS, Fonov VS, Mathieu A, Aliaga A, Kostikov A, Do Carmo S, Dea D, Poirier J, Soucy JP, Gauthier S, Cuello AC, Rosa-Neto P (2017) Multimodal imaging in rat model recapitulates Alzheimer’s disease biomarkers abnormalities. J Neurosci 37:12263–12271.  https://doi.org/10.1523/JNEUROSCI.1346-17.2017 CrossRefGoogle Scholar
  22. 22.
    Mustard JF, Kinlough-Rathbone RL, Packham MA (1989) Isolation of human platelets from plasma by centrifugation and washing. Methods Enzymol 169:3–11CrossRefGoogle Scholar
  23. 23.
    Garcia-Manzano A, Gonzalez-Llaven J, Lemini C, Rubio-Poo C (2001) Standardization of rat blood clotting tests with reagents used for humans. Proc West Pharmacol Soc 44:153–155Google Scholar
  24. 24.
    Rivadeneyra L, Carestia A, Etulain J, Pozner RG, Fondevila C, Negrotto S, Schattner M (2014) Regulation of platelet responses triggered by Toll-like receptor 2 and 4 ligands is another non-genomic role of nuclear factor-kappaB. Thromb Res 133:235–243.  https://doi.org/10.1016/j.thromres.2013.11.028 CrossRefGoogle Scholar
  25. 25.
    Terada H (1990) Uncouplers of oxidative phosphorylation. Environ Health Perspect 87:213–218.  https://doi.org/10.1289/ehp.9087213 CrossRefGoogle Scholar
  26. 26.
    Brand MD, Nicholls DG (2011) Assessing mitochondrial dysfunction in cells. Biochem J 435:297–312.  https://doi.org/10.1042/BJ20110162 CrossRefGoogle Scholar
  27. 27.
    Galeano P, Martino Adami PV, Do Carmo S, Blanco E, Rotondaro C, Capani F, Castano EM, Cuello AC, Morelli L (2014) Longitudinal analysis of the behavioral phenotype in a novel transgenic rat model of early stages of Alzheimer’s disease. Front Behav Neurosci 8:321.  https://doi.org/10.3389/fnbeh.2014.00321 CrossRefGoogle Scholar
  28. 28.
    Martino Adami PV, Quijano C, Magnani N, Galeano P, Evelson P, Cassina A, Do Carmo S, Leal MC, Castano EM, Cuello AC, Morelli L (2017) Synaptosomal bioenergetic defects are associated with cognitive impairment in a transgenic rat model of early Alzheimer’s disease. J Cereb Blood Flow Metab 37:69–84.  https://doi.org/10.1177/0271678X15615132 CrossRefGoogle Scholar
  29. 29.
    Hall H, Iulita MF, Gubert P, Flores Aguilar L, Ducatenzeiler A, Fisher A, Cuello AC (2018) AF710B, an M1/sigma-1 receptor agonist with long-lasting disease-modifying properties in a transgenic rat model of Alzheimer’s disease. Alzheimers Dement 14:811–823.  https://doi.org/10.1016/j.jalz.2017.11.009 CrossRefGoogle Scholar
  30. 30.
    Iulita MF, Bistue Millon MB, Pentz R, Aguilar LF, Do Carmo S, Allard S, Michalski B, Wilson EN, Ducatenzeiler A, Bruno MA, Fahnestock M, Cuello AC (2017) Differential deregulation of NGF and BDNF neurotrophins in a transgenic rat model of Alzheimer’s disease. Neurobiol Dis 108:307–323.  https://doi.org/10.1016/j.nbd.2017.08.019 CrossRefGoogle Scholar
  31. 31.
    Wilson EN, Abela AR, Do Carmo S, Allard S, Marks AR, Welikovitch LA, Ducatenzeiler A, Chudasama Y, Cuello AC (2017) Intraneuronal amyloid beta accumulation disrupts hippocampal CRTC1-dependent gene expression and cognitive function in a rat model of Alzheimer disease. Cereb Cortex 27:1501–1511.  https://doi.org/10.1093/cercor/bhv332 Google Scholar
  32. 32.
    Heggland I, Storkaas IS, Soligard HT, Kobro-Flatmoen A, Witter MP (2015) Stereological estimation of neuron number and plaque load in the hippocampal region of a transgenic rat model of Alzheimer’s disease. Eur J Neurosci 41:1245–1262.  https://doi.org/10.1111/ejn.12876 CrossRefGoogle Scholar
  33. 33.
    Pimentel LS, Allard S, Do Carmo S, Weinreb O, Danik M, Hanzel CE, Youdim MB, Cuello AC (2015) The multi-target drug M30 shows pro-cognitive and anti-inflammatory effects in a rat model of Alzheimer’s disease. J Alzheimers Dis 47:373–383.  https://doi.org/10.3233/JAD-143126 CrossRefGoogle Scholar
  34. 34.
    Hanzel CE, Pichet-Binette A, Pimentel LS, Iulita MF, Allard S, Ducatenzeiler A, Do Carmo S, Cuello AC (2014) Neuronal driven pre-plaque inflammation in a transgenic rat model of Alzheimer’s disease. Neurobiol Aging 35:2249–2262.  https://doi.org/10.1016/j.neurobiolaging.2014.03.026 CrossRefGoogle Scholar
  35. 35.
    Iulita MF, Allard S, Richter L, Munter LM, Ducatenzeiler A, Weise C, Do Carmo S, Klein WL, Multhaup G, Cuello AC (2014) Intracellular Abeta pathology and early cognitive impairments in a transgenic rat overexpressing human amyloid precursor protein: a multidimensional study. Acta Neuropathol Commun 2:61.  https://doi.org/10.1186/2051-5960-2-61 CrossRefGoogle Scholar
  36. 36.
    He Q, Su G, Liu K, Zhang F, Jiang Y, Gao J, Liu L, Jiang Z, Jin M, Xie H (2017) Sex-specific reference intervals of hematologic and biochemical analytes in Sprague-Dawley rats using the nonparametric rank percentile method. PLoS ONE 12:e0189837.  https://doi.org/10.1371/journal.pone.0189837 CrossRefGoogle Scholar
  37. 37.
    Ravi S, Chacko B, Sawada H, Kramer PA, Johnson MS, Benavides GA, O’Donnell V, Marques MB, Darley-Usmar VM (2015) Metabolic plasticity in resting and thrombin activated platelets. PLoS ONE 10:e0123597.  https://doi.org/10.1371/journal.pone.0123597 CrossRefGoogle Scholar
  38. 38.
    Fisar Z, Hroudova J, Hansikova H, Spacilova J, Lelkova P, Wenchich L, Jirak R, Zverova M, Zeman J, Martasek P, Raboch J (2016) Mitochondrial respiration in the platelets of patients with Alzheimer’s disease. Curr Alzheimer Res 13:930–941.  https://doi.org/10.2174/1567205013666160314150856 CrossRefGoogle Scholar
  39. 39.
    Xu W, Cardenes N, Corey C, Erzurum SC, Shiva S (2015) Platelets from asthmatic individuals show less reliance on glycolysis. PLoS ONE 10:e0132007.  https://doi.org/10.1371/journal.pone.0132007 CrossRefGoogle Scholar
  40. 40.
    Schoenwaelder SM, Darbousset R, Cranmer SL, Ramshaw HS, Orive SL, Sturgeon S, Yuan Y, Yao Y, Krycer JR, Woodcock J, Maclean J, Pitson S, Zheng Z, Henstridge DC, van der Wal D, Gardiner EE, Berndt MC, Andrews RK, James DE, Lopez AF, Jackson SP (2016) 14-3-3zeta regulates the mitochondrial respiratory reserve linked to platelet phosphatidylserine exposure and procoagulant function. Nat Commun 7:12862.  https://doi.org/10.1038/ncomms12862 CrossRefGoogle Scholar
  41. 41.
    Gabbita SP, Lovell MA, Markesbery WR (1998) Increased nuclear DNA oxidation in the brain in Alzheimer’s disease. J Neurochem 71:2034–2040.  https://doi.org/10.1046/j.1471-4159.1998.71052034.x CrossRefGoogle Scholar
  42. 42.
    Pfleger J, He M, Abdellatif M (2015) Mitochondrial complex II is a source of the reserve respiratory capacity that is regulated by metabolic sensors and promotes cell survival. Cell Death Dis 6:e1835.  https://doi.org/10.1038/cddis.2015.202 CrossRefGoogle Scholar
  43. 43.
    Sriskanthadevan S, Jeyaraju DV, Chung TE, Prabha S, Xu W, Skrtic M, Jhas B, Hurren R, Gronda M, Wang X, Jitkova Y, Sukhai MA, Lin FH, Maclean N, Laister R, Goard CA, Mullen PJ, Xie S, Penn LZ, Rogers IM, Dick JE, Minden MD, Schimmer AD (2015) AML cells have low spare reserve capacity in their respiratory chain that renders them susceptible to oxidative metabolic stress. Blood 125:2120–2130.  https://doi.org/10.1182/blood-2014-08-594408 CrossRefGoogle Scholar
  44. 44.
    Hill BG, Dranka BP, Zou L, Chatham JC, Darley-Usmar VM (2009) Importance of the bioenergetic reserve capacity in response to cardiomyocyte stress induced by 4-hydroxynonenal. Biochem J 424:99–107.  https://doi.org/10.1042/BJ20090934 CrossRefGoogle Scholar
  45. 45.
    Niu X, Whisson ME, Guppy M (1997) Types and sources of fuels for platelets in a medium containing minimal added fuels and a low carryover plasma. Br J Haematol 97:908–916.  https://doi.org/10.1046/j.1365-2141.1997.1442963.x CrossRefGoogle Scholar
  46. 46.
    Derksen A, Cohen P (1975) Patterns of fatty acid release from endogenous substrates by human platelet homogenates and membranes. J Biol Chem 250:9342–9347Google Scholar
  47. 47.
    Wanders RJ, Vreken P, Ferdinandusse S, Jansen GA, Waterham HR, van Roermund CW, Van Grunsven EG (2001) Peroxisomal fatty acid alpha- and beta-oxidation in humans: enzymology, peroxisomal metabolite transporters and peroxisomal diseases. Biochem Soc Trans 29:250–267.  https://doi.org/10.1042/bst0290250 CrossRefGoogle Scholar
  48. 48.
    Marnett LJ, Rowlinson SW, Goodwin DC, Kalgutkar AS, Lanzo CA (1999) Arachidonic acid oxygenation by COX-1 and COX-2. Mechanisms of catalysis and inhibition. J Biol Chem 274:22903–22906.  https://doi.org/10.1074/jbc.274.33.22903 CrossRefGoogle Scholar
  49. 49.
    Halestrap AP (2006) Calcium, mitochondria and reperfusion injury: a pore way to die. Biochem Soc Trans 34:232–237.  https://doi.org/10.1042/BST20060232 CrossRefGoogle Scholar
  50. 50.
    Halestrap AP, Clarke SJ, Javadov SA (2004) Mitochondrial permeability transition pore opening during myocardial reperfusion–a target for cardioprotection. Cardiovasc Res 61:372–385.  https://doi.org/10.1016/S0008-6363(03)00533-9 CrossRefGoogle Scholar
  51. 51.
    Fraser PE, Nguyen JT, Inouye H, Surewicz WK, Selkoe DJ, Podlisny MB, Kirschner DA (1992) Fibril formation by primate, rodent, and Dutch-hemorrhagic analogues of Alzheimer amyloid beta-protein. Biochemistry 31:10716–10723CrossRefGoogle Scholar
  52. 52.
    Wilson EN, Carmo SD, Iulita MF, Hall H, Austin GL, Jia DT, Malcolm JC, Foret MK, Marks A, Butterfield DA, Cuello AC (2018) Microdose lithium NP03 diminishes pre-Plaque oxidative damage and neuroinflammation in a rat model of Alzheimer’s-like amyloidosis. Curr Alzheimer Res.  https://doi.org/10.2174/1567205015666180904154446 Google Scholar
  53. 53.
    Banks WA (2008) Blood–brain barrier transport of cytokines. In: Phelps C, Korneva E (eds) NeuroImmune biology. Elsevier Science, Amsterdam, pp 93–106Google Scholar
  54. 54.
    De Biase L, Pignatelli P, Lenti L, Tocci G, Piccioni F, Riondino S, Pulcinelli FM, Rubattu S, Volpe M, Violi F (2003) Enhanced TNF alpha and oxidative stress in patients with heart failure: effect of TNF alpha on platelet O2-production. Thromb Haemost 90:317–325.  https://doi.org/10.1160/TH03-02-0105 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Laboratory of Amyloidosis and NeurodegenerationFundación Instituto Leloir, IIBBA-CONICETCiudad Autónoma de Buenos AiresArgentina
  2. 2.Department of Pharmacology and TherapeuticsMcGill UniversityMontrealCanada

Personalised recommendations