Abstract
In the aging world population, Alzheimer’s disease accounts for more than 70% of all cases of dementia and is the sixth leading cause of death. The neurodegenerative processes of this disorder can begin 10–20 years before the clinical symptoms develop. Postmortem brain autopsy of Alzheimer’s disease cases reveals characteristic hallmarks like extracellular amyloid plaques and intraneuronal neurofibrillary tangles and synaptic and neuronal disintegration with severe brain atrophy. Some studies have reported that platelets contain the amyloid protein precursor and the secretase enzymes required for the amyloidogenic processing of this protein. Thus, platelets can be a good blood cell-based marker to investigate the onset of Alzheimer’s disease. Other studies have indicated cellular and molecular alterations in erythrocytes and lymphocytes from Alzheimer’s disease subjects, which emphasize the systemic nature of the disorder. In addition, small extracellular vesicles called exosomes appear to be an important factor during the progression of the disease. These vesicles contain disease-associated molecules such as the amyloid protein precursor and tau protein. In this chapter, we will summarize the recent knowledge on the involvement of lymphocytes, erythrocytes, platelets, and exosomes in the development of Alzheimer’s disease. The data will be reviewed with a view to applying the above elements as Alzheimer’s disease early preclinical and late-stage biomarkers with potential use for clinical diagnosis, prognosis, and monitoring disease progression and treatment responses.
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Engedal K, Barca ML, Laks J, Selbaek G (2011) Depression in Alzheimer’s disease: specificity of depressive symptoms using three different clinical criteria. Int J Geriatr Psychiatry 26:944–951
Villemagne VL, Pike KE, Chetelat G, Ellis KA, Mulligan RS, Bourgeat P et al (2011) Longitudinal assessment of Abeta and cognition in aging and Alzheimer disease. Ann Neurol 69:181–192
Villemagne VL, Burnham S, Bourgeat P, Brown B, Ellis KA, Salvado O et al (2013) Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol 12:357–367
Rushing NC, Sachs-Ericsson N, Steffens DC (2014) Neuropsychological indicators of preclinical Alzheimer’s disease among depressed older adults. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn 21:99–128
Zhao QF, Tan L, Wang HF, Jiang T, Tan MS, Tan L et al (2016) The prevalence of neuropsychiatric symptoms in Alzheimer’s disease: systematic review and meta-analysis. J Affect Disord 190:264–271
Landeiro F, Walsh K, Ghinai I, Mughal S, Nye E, Wace H et al (2018) Measuring quality of life of people with predementia and dementia and their caregivers: a systematic review protocol. BMJ Open 8:e019082. https://doi.org/10.1136/bmjopen-2017-019082
www.alz.org. 2018
Hu Z, Zeng L, Huang Z, Zhang J, Li T (2007) The study of Golgi apparatus in Alzheimer’s disease. Neurochem Res 32:1265–1277
Hebert LE, Beckett LA, Scherr PA, Evans DA (2001) Annual incidence of Alzheimer disease in the United States projected to the years 2000 through 2050. Alzheimer Dis Assoc Disord 15:169–173
Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP (2013) The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement 9:63–75.e62. https://doi.org/10.1016/j.jalz.2012.11.007
Winblad B, Amouyel P, Andrieu S, Ballard C, Brayne C, Brodaty H et al (2016) Defeating Alzheimer’s disease and other dementias: a priority for European science and society. Lancet Neurol 15:455–532
Canobbio I, Abubaker AA, Visconte C, Torti M, Pula G (2015) Role of amyloid peptides in vascular dysfunction and platelet dysregulation in Alzheimer’s disease. Front Cell Neurosci 9:65. https://doi.org/10.3389/fncel.2015.00065
Pluta R, Furmaga-Jabłońska W, Maciejewski R, Ułamek-Kozioł M, Jabłoński M (2013) Brain ischemia activates β- and γ-secretase cleavage of amyloid precursor protein: significance in sporadic Alzheimer’s disease. Mol Neurobiol 47:425–434
Pluta R, Jabłoński M, Ułamek-Kozioł M, Kocki J, Brzozowska J, Januszewski S et al (2013) Sporadic Alzheimer’s disease begins as episodes of brain ischemia and ischemically dysregulated Alzheimer’s disease genes. Mol Neurobiol 48:500–515
Pluta R, Ułamek-Kozioł M, Januszewski S, Czuczwar SJ (2018) Platelets, lymphocytes and erythrocytes from Alzheimer’s disease patients: the quest for blood cell-based biomarkers. Folia Neuropathol 56:14–20
Scheltens P, Blennow K, Breteler MM, de Strooper B, Frisoni GB, Salloway S et al (2016) Alzheimer’s disease. Lancet 388:505–517
Pluta R, Kida E, Lossinsky AS, Golabek AA, Mossakowski MJ, Wisniewski HM (1994) Complete cerebral ischemia with short-term survival in rats induced by cardiac arrest. I. Extracellular accumulation of Alzheimer’s β-amyloid protein precursor in the brain. Brain Res 649:323–328
Pluta R (2007) Ischemia-reperfusion pathways in Alzheimer’s disease. Nova Science Publisher, Inc., New York ISBN-10:1600217443
Pluta R, Ułamek M, Jabłoński M (2009) Alzheimer’s mechanisms in ischemic brain degeneration. Anat Rec 292:1863–1881
Kocki J, Ułamek-Kozioł M, Bogucka-Kocka A, Januszewski S, Jabłoński M, Gil-Kulik P et al (2015) Dysregulation of amyloid precursor protein, β-secretase, presenilin 1 and 2 genes in the rat selectively vulnerable CA1 subfield of hippocampus following transient global brain ischemia. J Alzheimers Dis 47:1047–1056
Pluta R, Kocki J, Ułamek-Kozioł M, Bogucka-Kocka A, Gil-Kulik P, Januszewski S et al (2016) Alzheimer-associated presenilin 2 gene is dysregulated in rat medial temporal lobe cortex after complete brain ischemia due to cardiac arrest. Pharmacol Rep 68:155–161
Pluta R, Kocki J, Ułamek-Kozioł M, Petniak A, Gil-Kulik P, Januszewski S et al (2016) Discrepancy in expression of β-secretase and amyloid-β protein precursor in Alzheimer-related genes in the rat medial temporal lobe cortex following transient global brain ischemia. J Alzheimers Dis 51:1023–1031
Ułamek-Kozioł M, Kocki J, Bogucka-Kocka A, Petniak A, Gil-Kulik P, Januszewski S et al (2016) Dysregulation of autophagy, mitophagy and apoptotic genes in the medial temporal lobe cortex in an ischemic model of Alzheimer’s disease. J Alzheimers Dis 54:113–121
Ułamek-Kozioł M, Kocki J, Bogucka-Kocka A, Januszewski S, Bogucki J, Czuczwar SJ et al (2017) Autophagy, mitophagy and apoptotic gene changes in the hippocampal CA1 area in a rat ischemic model of Alzheimer’s disease. Pharmacol Rep 69:1289–1294
Pluta R, Bogucka-Kocka A, Ułamek-Kozioł M, Bogucki J, Januszewski S, Kocki J et al (2018) Ischemic tau protein gene induction as an additional key factor driving development of Alzheimer’s phenotype changes in CA1 area of hippocampus in an ischemic model of Alzheimer’s disease. Pharmacol 70:881–884
Schaffer C, Sarad N, DeCrumpe A, Goswami D, Herrmann S, Morales J et al (2015) Biomarkers in the diagnosis and prognosis of Alzheimer’s disease. J Lab Autom 20:589–600
McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH 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. Alzheimers Dement 7:263–269
Blennow K, Hampel H, Weiner M, Zetterberg H (2010) Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol 6:131–144
Fiandaca MS, Kapogiannis D, Mapstone M, Boxer A, Eitan E, Schwartz JB et al (2014) Identification of preclinical Alzheimer’s disease by a profile of pathogenic proteins in neurally derived blood exosomes: a case-control study. Alzheimers Dement 11:600–607
Seeburger JL, Holder DJ, Combrinck M, Joachim C, Laterza O, Tanen M et al (2015) Cerebrospinal fluid biomarkers distinguish postmortem-confirmed Alzheimer’s disease from other dementias and healthy controls in the optima cohort. J Alzheimers Dis 44:525–539
Perneczky R, Guo LH (2016) Plasma proteomics biomarkers in Alzheimer’s disease: latest advances and challenges. Methods Mol Biol 1303:521–529
Mietelska-Porowska A, Wojda U (2017) T lymphocytes and inflammatory mediators in the interplay between brain and blood in Alzheimer’s disease: potential pools of new biomarkers. J Immunol Res 17. https://doi.org/10.1155/2017/4626540
Stevenson A, Lopez D, Khoo P, Kalaria RN, Mukaetova-Ladinska EB (2017) Exploring erythrocytes as blood biomarkers for Alzheimer’s disease. J Alzheimers Dis 60:845–857
Wojsiat J, Laskowska-Kaszub K, Mietelska-Porowska A, Wojda U (2017) Search for Alzheimer’s disease biomarkers in blood cells: hypotheses-driven approach. Biomark Med 11:917–931
Vella LJ, Hill AF, Cheng L (2016) Focus on extracellular vesicles: exosomes and their role in protein trafficking and biomarker potential in Alzheimer’s and Parkinson’s disease. Int J Mol Sci 17:173. https://doi.org/10.3390/ijms17020173
Yuyama K, Igarashi Y (2017) Exosomes as carriers of Alzheimer’s amyloid-β. Front Neurosci 11:229. https://doi.org/10.3389/fnins.2017.00229
Veitinger M, Varga B, Guterres SB, Zellner M (2014) Platelets, a reliable source for peripheral Alzheimer’s disease biomarkers? Acta Neuropathol Commun 2:65. https://doi.org/10.1186/2051-5960-2-65
Sakurai H, Hanyu H, Sato T, Kume K, Hirao K, Kanetaka H et al (2013) Effects of cilostazol on cognition and regional cerebral blood flow in patients with Alzheimer’s disease and cerebrovascular disease: a pilot study. Geriatr Gerontol Int 13:90–97
Prodan CI, Szasz R, Vincent AS, Ross ED, Dale GL (2006) Coated platelets retain amyloid precursor protein on their surface. Platelets 17:56–60
Prodan CI, Ross ED, Vincent AS, Dale GL (2008) Rate of progression in Alzheimer’s disease correlates with coated-platelet levels–a longitudinal study. Transl Res 152:99–102
Neumann K, Farias G, Slachevsky A, Perez P, Maccioni RB (2011) Human platelet tau: a potential peripheral marker for Alzheimer’s disease. J Alzheimers Dis 25:103–109
Farias G, Perez P, Slachevsky A, Maccioni RB (2012) Platelet tau pattern correlates with cognitive status in Alzheimer’s disease. J Alzheimers Dis 31:65–69
Slachevsky A, Guzman-Martınez L, Delgado C, Reyes P, Farıas GA, Munoz-Neira C et al (2017) Tau platelets correlate with regional brain atrophy in patients with Alzheimer’s disease. J Alzheimers Dis 55:1595–1603
Mota SI, Costa RO, Ferreira IL, Santana I, Caldeira GL, Padovano C et al (2015) Oxidative stress involving changes in Nrf2 and ER stress in early stages of Alzheimer’s disease. Biochim Biophys Acta 1852:1428–1441
Wojsiat J, Prandelli C, Laskowska-Kaszub K, Martín Requero A, Wojda U (2015) Oxidative stress and aberrant cell cycle in Alzheimer’s disease lymphocytes: diagnostic prospects. J Alzheimers Dis 46:329–350
Wojda U (2016) Alzheimer’s disease lymphocytes: potential for biomarkers. Biomark Med 10:1–4
Kuhla A, Ludwig SC, Kuhla B, Münch G, Vollmar B (2015) Advanced glycation end products are mitogenic signals and trigger cell cycle reentry of neurons in Alzheimer’s disease brain. Neurobiol Aging 36:753–761
Zhang J, Kong Q, Zhang Z, Ge P, Ba D, He W (2003) Telomere dysfunction of lymphocytes in patients with Alzheimer disease. Cogn Behav Neurol 16:170–176
Richartz-Salzburger E, Batra A, Stransky E, Laske C, Köhler N, Bartels M et al (2007) Altered lymphocyte distribution in Alzheimer’s disease. J Psychiatr Res 41:174–178
Da Mesquita SA, Ferreira C, Sousa JC, Correia-Neves M, Sousa N, Marques F (2016) Insights on the pathophysiology of Alzheimer’s disease: the crosstalk between amyloid pathology, neuroinflammation and the peripheral immune system. Neurosci Biobehav Rev 68:547–562
Licastro F, Porcellini E (2016) Persistent infections, immune-senescence and Alzheimer’s disease. Oncoscience 3:135–142
Schwartz M, Deczkowska A (2016) Neurological disease as a failure of brain-immune crosstalk: the multiple faces of neuroinflammation. Trends Immunol 37:668–679
Deardorff WJ, Grossberg GT (2017) Targeting neuroinflammation in Alzheimer’s disease: evidence for NSAIDs and novel therapeutics. Expert Rev Neurother 17:17–32
Kiko T, Nakagawa K, Satoh A, Tsuduki T, Furukawa K, Arai H et al (2012) Amyloid beta levels in human red blood cells. PLoS One 7(11):e49620. https://doi.org/10.1371/journal.pone.0049620
Nakagawa K, Kiko T, Kuriwada S, Miyazawa T, Kimura F, Miyazawa T (2011) Amyloid β induces adhesion of erythrocytes to endothelial cells and affects endothelial viability and functionality. Biosci Biotechnol Biochem 75:2030–2033
Nakagawa K, Kiko T, Miyazawa T, Sookwong P, Tsuduki T, Satoh A et al (2011) Amyloid β-induced erythrocytic damage and its attenuation by carotenoids. FEBS Lett 585:1249–1254
Street JM, Barran PE, Mackay CL, Weidt S, Balmforth C, Walsh TS et al (2012) Identification and proteomic profiling of exosomes in human cerebrospinal fluid. J Transl Med 10. https://doi.org/10.1186/1479-5876-10-5
Cheng L, Sun X, Scicluna BJ, Coleman BM, Hill AF (2013) Characterization and deep sequencing analysis of exosomal and non-exosomal miRNA in human urine. Kidney Int 86:433–444
Cheng L, Sharples RA, Scicluna BJ, Hill AF (2014) Exosomes provide a protective and enriched source of miRNA for biomarker profiling compared to intracellular and cell-free blood. J Extracell Vesicles 3. https://doi.org/10.3402/jev.v3.23743
Kalra H, Drummen GPC, Mathivanan S (2016) Focus on extracellular vesicles: introducing the next small big thing. Int J Mol Sci 17:170. https://doi.org/10.3390/ijms17020170
Chiasserini D, van Weering JR, Piersma SR, Pham TV, Malekzadeh A, Teunissen CE et al (2014) Proteomic analysis of cerebrospinal fluid extracellular vesicles: a comprehensive dataset. J Proteome 106:191–204
Saman S, Kim W, Raya M, Visnick Y, Miro S, Saman S et al (2012) Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease. J Biol Chem 287:3842–3849
Lopez-Font I, Cuchillo-Ibanez I, Sogorb-Esteve A, Garcia-Ayllon MS, Saez-Valero J (2015) Transmembrane amyloid-related proteins in CSF as potential biomarkers for Alzheimer’s disease. Front Neurol 6:125. https://doi.org/10.3389/fneur.2015.00125
Cheng L, Doecke JD, Sharples RA, Villemagne VL, Fowler CJ, Rembach A et al (2014) Prognostic serum miRNA biomarkers associated with Alzheimer’s disease shows concordance with neuropsychological and neuroimaging assessment. Mol Psychiatry 20:1188–1196
Vingtdeux V, Sergeant N, Buee L (2012) Potential contribution of exosomes to the prion-like propagation of lesions in Alzheimer’s disease. Front Physiol 3:229. https://doi.org/10.3389/fphys.2012.00229
Hamaguchi T, Eisele YS, Varvel NH, Lamb BT, Walker LC, Jucker M (2012) The presence of Aβ seeds, and not age per se, is critical to the initiation of Aβ deposition in the brain. Acta Neuropathol 123:31–37
Nath S, Agholme L, Kurudenkandy FR, Granseth B, Marcusson J, Hallbeck M (2012) Spreading of neurodegenerative pathology via neuron-to-neuron transmission of β-amyloid. J Neurosci 32:8767–8777
Domert J, Rao SB, Agholme L, Brorsson AC, Marcusson J, Hallbeck M et al (2014) Spreading of amyloid-β peptides via neuritic cell-to-cell transfer is dependent on insufficient cellular clearance. Neurobiol Dis 65:82–92
Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A et al (2009) Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 11:909–913
Liu L, Drouet V, Wu JW, Witter MP, Small SA, Clelland C et al (2012) Trans-synaptic spread of tau pathology in vivo. PLoS One 7:e31302. doi: 10.1371/journal.pone.0031302
Heneka TM, Carson MJ, Khoury JE, Landreth GE, Brosseron F, Feinstein DL et al (2015) Neuroinflammation in Alzheimer’s disease. Lancet Neurol 14:388–405
Ghidoni R, Squitti R, Siotto M, Benussi L (2018) Innovative biomarkers for Alzheimer’s disease: focus on the hidden disease biomarkers. J Alzheimers Dis 62:1507–1518
Polanco JC, Li C, Durisic N, Sullivan R, Götz J (2018) Exosomes taken up by neurons hijack the endosomal pathway to spread to interconnected neurons. Acta Neuropathol Commun 6(1):10. https://doi.org/10.1186/s40478-018-0514-4
Zheng T, Wu X, Wei X, Wang M, Zhang B (2018) The release and transmission of amyloid precursor protein via exosomes. Neurochem Int 114:18–253
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The authors acknowledge the support provided by the Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland (T3).
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Pluta, R., Ułamek-Kozioł, M. (2019). Lymphocytes, Platelets, Erythrocytes, and Exosomes as Possible Biomarkers for Alzheimer’s Disease Clinical Diagnosis. In: Guest, P. (eds) Reviews on Biomarker Studies in Psychiatric and Neurodegenerative Disorders. Advances in Experimental Medicine and Biology(), vol 1118. Springer, Cham. https://doi.org/10.1007/978-3-030-05542-4_4
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