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DOI: 10.1055/s-0044-1779296
Extracellular vesicles in Alzheimer's disease
Vesículas extracelulares na doença de AlzheimerAbstract
Extracellular vesicles (EVs) are small vesicles released by cells that facilitate cell signaling. They are categorized based on their biogenesis and size. In the context of the central nervous system (CNS), EVs have been extensively studied for their role in both normal physiological functions and diseases like Alzheimer's disease (AD). AD is a neurodegenerative disorder characterized by cognitive decline and neuronal death. EVs have emerged as potential biomarkers for AD due to their involvement in disease progression. Specifically, EVs derived from neurons, astrocytes, and neuron precursor cells exhibit changes in quantity and composition in AD. Neuron-derived EVs have been found to contain key proteins associated with AD pathology, such as amyloid beta (Aß) and tau. Increased levels of Aß in neuron-derived EVs isolated from the plasma have been observed in individuals with AD and mild cognitive impairment, suggesting their potential as early biomarkers. However, the analysis of tau in neuron-derived EVs is still inconclusive. In addition to Aß and tau, neuron-derived EVs also carry other proteins linked to AD, including synaptic proteins. These findings indicate that EVs could serve as biomarkers for AD, particularly for early diagnosis and disease monitoring. However, further research is required to validate their use and explore potential therapeutic applications. To summarize, EVs are small vesicles involved in cell signaling within the CNS. They hold promise as biomarkers for AD, potentially enabling early diagnosis and monitoring of disease progression. Ongoing research aims to refine their use as biomarkers and uncover additional therapeutic applications.
Resumo
As vesículas extracelulares (VEs) são pequenas estruturas liberadas pelas células que agem na sinalização celular. No sistema nervoso central (SNC), as VEs são estudadas em relação à doença de Alzheimer (DA), um distúrbio neurodegenerativo que cursa com declínio cognitivo e morte neuronal. As VEs podem ser biomarcadores potenciais para a DA devido ao seu papel na progressão da doença. As VEs derivadas de neurônios, astrócitos e células precursoras apresentam alterações na DA, contendo proteínas associadas à patologia da DA, como beta-amiloide (Aß) e tau. Níveis elevados de Aß foram observados nas VEs de neurônios de indivíduos com DA, sugerindo seu potencial como biomarcadores precoces. A análise de tau nas VEs de neurônios ainda é inconclusiva. Além disso, as VEs neurais carregam outras proteínas relacionadas à DA, incluindo proteínas sinápticas. As VEs podem ser promissoras como biomarcadores para o diagnóstico precoce e monitoramento da DA, porém mais pesquisas são necessárias para validar seu uso e explorar aplicações terapêuticas. Em resumo, as VEs são vesículas envolvidas na sinalização celular no SNC, com potencial como biomarcadores para a DA.
Keywords
Extracellular Vesicles - Central Nervous System - Alzheimer Disease - Biomarkers - Early Diagnosis - Signal TransductionPalavras-chave
Vesículas Extracelulares - Sistema Nervoso Central - Doença de Alzheimer - Biomarcadores - Diagnóstico Precoce - Transdução de SinaisAuthors' Contributions
VHBP: conceptualization, investigation, methodology, writing – original draft, writing – review & editing; JPLD: conceptualization, data curation, formal analysis, funding acquisition, investigation, methodology, project administration, resources, supervision, validation, visualization, writing – original draft, writing – review & editing; SK, TM: conceptualization, data curation, formal analysis, funding acquisition, investigation, methodology, project administration, resources, software, supervision, validation, visualization, writing – original draft, writing – review & editing.
Publication History
Received: 15 June 2023
Accepted: 01 December 2023
Article published online:
11 March 2024
© 2024. Academia Brasileira de Neurologia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/)
Thieme Revinter Publicações Ltda.
Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil
Victor Hugo Berriel Pinho, João Paulo Lima Daher, Salim Kanaan, Thalia Medeiros. Extracellular vesicles in Alzheimer's disease. Arq Neuropsiquiatr 2024; 82: s00441779296.
DOI: 10.1055/s-0044-1779296
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References
- 1 Théry C, Witwer KW, Aikawa E. et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles 2018; 7 (01) 1535750 DOI: 10.1080/20013078.2018.1535750.
- 2 Théry C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 2009; 9 (08) 581-593 DOI: 10.1038/nri2567.
- 3 Denzer K, Kleijmeer MJ, Heijnen HF, Stoorvogel W, Geuze HJ. Exosome: from internal vesicle of the multivesicular body to intercellular signaling device. J Cell Sci 2000; 113 (Pt 19): 3365-3374 DOI: 10.1242/jcs.113.19.3365.
- 4 György B, Szabó TG, Pásztói M. et al. Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Cell Mol Life Sci 2011; 68 (16) 2667-2688 DOI: 10.1007/s00018-011-0689-3.
- 5 Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol 2013; 200 (04) 373-383 DOI: 10.1083/jcb.201211138.
- 6 Théry C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol 2002; 2 (08) 569-579 DOI: 10.1038/nri855.
- 7 Shah R, Patel T, Freedman JE. Circulating Extracellular Vesicles in Human Disease. N Engl J Med 2018; 379 (10) 958-966 DOI: 10.1056/NEJMra1704286.
- 8 Raposo G, Nijman HW, Stoorvogel W. et al. B lymphocytes secrete antigen-presenting vesicles. J Exp Med 1996; 183 (03) 1161-1172
- 9 Robbins PD, Dorronsoro A, Booker CN. Regulation of chronic inflammatory and immune processes by extracellular vesicles. J Clin Invest 2016; 126 (04) 1173-1180
- 10 Colombo M, Raposo G, Théry C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol 2014; 30: 255-289 DOI: 10.1146/annurev-cellbio-101512-122326.
- 11 Fauré J, Lachenal G, Court M. et al. Exosomes are released by cultured cortical neurones. Mol Cell Neurosci 2006; 31 (04) 642-648 DOI: 10.1016/j.mcn.2005.12.003.
- 12 Morel L, Regan M, Higashimori H. et al. Neuronal exosomal miRNA-dependent translational regulation of astroglial glutamate transporter GLT1. J Biol Chem 2013; 288 (10) 7105-7116 DOI: 10.1074/jbc.M112.410944.
- 13 Potolicchio I, Carven GJ, Xu X. et al. Proteomic analysis of microglia-derived exosomes: metabolic role of the aminopeptidase CD13 in neuropeptide catabolism. J Immunol 2005; 175 (04) 2237-2243 DOI: 10.4049/jimmunol.175.4.2237.
- 14 Krämer-Albers EM, Bretz N, Tenzer S. et al. Oligodendrocytes secrete exosomes containing major myelin and stress-protective proteins: Trophic support for axons?. Proteomics Clin Appl 2007; 1 (11) 1446-1461 DOI: 10.1002/prca.200700522.
- 15 Saeedi S, Israel S, Nagy C, Turecki G. The emerging role of exosomes in mental disorders. Transl Psychiatry 2019; 9 (01) 122 DOI: 10.1038/s41398-019-0459-9.
- 16 Chivet M, Javalet C, Hemming F. et al. Exosomes as a novel way of interneuronal communication. Biochem Soc Trans 2013; 41 (01) 241-244 DOI: 10.1042/BST20120266.
- 17 Goldie BJ, Dun MD, Lin M. et al. Activity-associated miRNA are packaged in Map1b-enriched exosomes released from depolarized neurons. Nucleic Acids Res 2014; 42 (14) 9195-9208 DOI: 10.1093/nar/gku594.
- 18 Yang Y, Gozen O, Vidensky S, Robinson MB, Rothstein JD. Epigenetic regulation of neuron-dependent induction of astroglial synaptic protein GLT1. Glia 2010; 58 (03) 277-286 DOI: 10.1002/glia.20922.
- 19 Hewett SJ, Jackman NA, Claycomb RJ. Interleukin-1β in Central Nervous System Injury and Repair. Eur J Neurodegener Dis 2012; 1 (02) 195-211
- 20 Bakhti M, Winter C, Simons M. Inhibition of myelin membrane sheath formation by oligodendrocyte-derived exosome-like vesicles. J Biol Chem 2011; 286 (01) 787-796 DOI: 10.1074/jbc.M110.190009.
- 21 Fröhlich D, Kuo WP, Frühbeis C. et al. Multifaceted effects of oligodendroglial exosomes on neurons: impact on neuronal firing rate, signal transduction and gene regulation. Philos Trans R Soc Lond B Biol Sci 2014; 369 (1652): 20130510 DOI: 10.1098/rstb.2013.0510.
- 22 Hill AF. Extracellular Vesicles and Neurodegenerative Diseases. J Neurosci 2019; 39 (47) 9269-9273 DOI: 10.1523/JNEUROSCI.0147-18.2019.
- 23 Hood JL, San RS, Wickline SA. Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. Cancer Res 2011; 71 (11) 3792-3801 DOI: 10.1158/0008-5472.CAN-10-4455.
- 24 Peinado H, Alečković M, Lavotshkin S. et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 2012; 18 (06) 883-891 DOI: 10.1038/nm.2753. Erratum in: Nat Med. 2016 Dec 6;22(12):1502. PMID: 22635005; PMCID: PMC3645291
- 25 Braak H, Rüb U, Gai WP, Del Tredici K. Idiopathic Parkinson's disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm (Vienna) 2003; 110 (05) 517-536 DOI: 10.1007/s00702-002-0808-2.
- 26 Ausó E, Gómez-Vicente V, Esquiva G. Biomarkers for Alzheimer's Disease Early Diagnosis. J Pers Med 2020; 10 (03) 114 DOI: 10.3390/jpm10030114.
- 27 Musunuri S, Khoonsari PE, Mikus M. et al. Increased Levels of Extracellular Microvesicle Markers and Decreased Levels of Endocytic/Exocytic Proteins in the Alzheimer's Disease Brain. J Alzheimers Dis 2016; 54 (04) 1671-1686 DOI: 10.3233/JAD-160271.
- 28 Badhwar A, Haqqani AS. Biomarker potential of brain-secreted extracellular vesicles in blood in Alzheimer's disease. Alzheimers Dement (Amst) 2020; 12 (01) e12001 DOI: 10.1002/dad2.12001.
- 29 Lugli G, Cohen AM, Bennett DA. et al. Plasma Exosomal miRNAs in Persons with and without Alzheimer Disease: Altered Expression and Prospects for Biomarkers. PLoS One 2015; 10 (10) e0139233 DOI: 10.1371/journal.pone.0139233.
- 30 Chivet M, Hemming F, Pernet-Gallay K, Fraboulet S, Sadoul R. Emerging role of neuronal exosomes in the central nervous system. Front Physiol 2012; 3: 145 DOI: 10.3389/fphys.2012.00145.
- 31 Peng KY, Pérez-González R, Alldred MJ. et al. Apolipoprotein E4 genotype compromises brain exosome production. Brain 2019; 142 (01) 163-175 DOI: 10.1093/brain/awy289.
- 32 Tran L, Ha-Duong T. Exploring the Alzheimer amyloid-β peptide conformational ensemble: A review of molecular dynamics approaches. Peptides 2015; 69: 86-91 DOI: 10.1016/j.peptides.2015.04.009.
- 33 Eftekharzadeh B, Daigle JG, Kapinos LE. et al. Tau Protein Disrupts Nucleocytoplasmic Transport in Alzheimer's Disease. Neuron 2018; 99 (05) 925-940.e7 DOI: 10.1016/j.neuron.2018.07.039. Erratum in: Neuron. 2019 Jan 16;101(2):349. PMID: 30189209; PMCID: PMC6240334
- 34 Chen JX, Yan SS. Role of mitochondrial amyloid-beta in Alzheimer's disease. J Alzheimers Dis 2010; 20 (Suppl. 02) S569-S578 DOI: 10.3233/JAD-2010-100357.
- 35 Crews L, Masliah E. Molecular mechanisms of neurodegeneration in Alzheimer's disease. Hum Mol Genet 2010; 19 (R1): R12-R20 DOI: 10.1093/hmg/ddq160.
- 36 Claeysen S, Cochet M, Donneger R, Dumuis A, Bockaert J, Giannoni P. Alzheimer culprits: cellular crossroads and interplay. Cell Signal 2012; 24 (09) 1831-1840 DOI: 10.1016/j.cellsig.2012.05.008.
- 37 Lee VM, Goedert M, Trojanowski JQ. Neurodegenerative tauopathies. Annu Rev Neurosci 2001; 24: 1121-1159 DOI: 10.1146/annurev.neuro.24.1.1121.
- 38 Jack Jr CR, Bennett DA, Blennow K. et al; Contributors. NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement 2018; 14 (04) 535-562 DOI: 10.1016/j.jalz.2018.02.018.
- 39 Jack Jr CR, Bennett DA, Blennow K. et al. A/T/N: An unbiased descriptive classification scheme for Alzheimer disease biomarkers. Neurology 2016; 87 (05) 539-547 DOI: 10.1212/WNL.0000000000002923.
- 40 Chen Z, Mengel D, Keshavan A. et al. Learnings about the complexity of extracellular tau aid development of a blood-based screen for Alzheimer's disease. Alzheimers Dement 2019; 15 (03) 487-496 DOI: 10.1016/j.jalz.2018.09.010.
- 41 Sato C, Barthélemy NR, Mawuenyega KG. et al. Tau Kinetics in Neurons and the Human Central Nervous System. Neuron 2018; 97 (06) 1284-1298.e7 DOI: 10.1016/j.neuron.2018.02.015. Erratum in: Neuron. 2018 May 16;98 (4):861–864. PMID: 29566794; PMCID: PMC6137722
- 42 Asai H, Ikezu S, Tsunoda S. et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci 2015; 18 (11) 1584-1593 DOI: 10.1038/nn.4132.
- 43 Sardar Sinha M, Ansell-Schultz A, Civitelli L. et al. Alzheimer's disease pathology propagation by exosomes containing toxic amyloid-beta oligomers. Acta Neuropathol 2018; 136 (01) 41-56 DOI: 10.1007/s00401-018-1868-1.
- 44 Jia L, Qiu Q, Zhang H. et al. Concordance between the assessment of Aβ42, T-tau, and P-T181-tau in peripheral blood neuronal-derived exosomes and cerebrospinal fluid. Alzheimers Dement 2019; 15 (08) 1071-1080 DOI: 10.1016/j.jalz.2019.05.002.
- 45 Winston CN, Goetzl EJ, Baker LD, Vitiello MV, Rissman RA. Growth Hormone-Releasing Hormone Modulation of Neuronal Exosome Biomarkers in Mild Cognitive Impairment. J Alzheimers Dis 2018; 66 (03) 971-981 DOI: 10.3233/JAD-180302.
- 46 Winston CN, Goetzl EJ, Akers JC. et al. Prediction of conversion from mild cognitive impairment to dementia with neuronally derived blood exosome protein profile. Alzheimers Dement (Amst) 2016; 3: 63-72 DOI: 10.1016/j.dadm.2016.04.001.
- 47 Fiandaca MS, Kapogiannis D, Mapstone M. et al. Identification of preclinical Alzheimer's disease by a profile of pathogenic proteins in neurally derived blood exosomes: A case-control study. Alzheimers Dement 2015; 11 (06) 600-7.e1 DOI: 10.1016/j.jalz.2014.06.008.
- 48 Eitan E, Hutchison ER, Marosi K. et al. Extracellular Vesicle-Associated Aβ Mediates Trans-Neuronal Bioenergetic and Ca2+-Handling Deficits in Alzheimer's Disease Models. NPJ Aging Mech Dis 2016; 2: 16019 DOI: 10.1038/npjamd.2016.19.
- 49 Shi M, Kovac A, Korff A. et al. CNS tau efflux via exosomes is likely increased in Parkinson's disease but not in Alzheimer's disease. Alzheimers Dement 2016; 12 (11) 1125-1131
- 50 Guix FX, Corbett GT, Cha DJ. et al. Detection of aggregation-competent tau in neuron-derived extracellular vesicles. Int J Mol Sci 2018; 19 (03) 663
- 51 Goetzl EJ, Kapogiannis D, Schwartz JB. et al. Decreased synaptic proteins in neuronal exosomes of frontotemporal dementia and Alzheimer's disease. FASEB J 2016; 30 (12) 4141-4148 DOI: 10.1096/fj.201600816R.
- 52 Agliardi C, Guerini FR, Zanzottera M, Bianchi A, Nemni R, Clerici M. SNAP-25 in Serum Is Carried by Exosomes of Neuronal Origin and Is a Potential Biomarker of Alzheimer's Disease. Mol Neurobiol 2019; 56 (08) 5792-5798 DOI: 10.1007/s12035-019-1501-x.
- 53 Goetzl EJ, Abner EL, Jicha GA, Kapogiannis D, Schwartz JB. Declining levels of functionally specialized synaptic proteins in plasma neuronal exosomes with progression of Alzheimer's disease. FASEB J 2018; 32 (02) 888-893 DOI: 10.1096/fj.201700731R.
- 54 Mullins RJ, Mustapic M, Goetzl EJ, Kapogiannis D. Exosomal biomarkers of brain insulin resistance associated with regional atrophy in Alzheimer's disease. Hum Brain Mapp 2017; 38 (04) 1933-1940 DOI: 10.1002/hbm.23494.
- 55 Kapogiannis D, Boxer A, Schwartz JB. et al. Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural-derived blood exosomes of preclinical Alzheimer's disease. FASEB J 2015; 29 (02) 589-596 DOI: 10.1096/fj.14-262048.
- 56 Goetzl EJ, Boxer A, Schwartz JB. et al. Altered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease. Neurology 2015; 85 (01) 40-47
- 57 Goetzl EJ, Nogueras-Ortiz C, Mustapic M. et al. Deficient neurotrophic factors of CSPG4-type neural cell exosomes in Alzheimer disease. FASEB J 2019; 33 (01) 231-238
- 58 Goetzl EJ, Schwartz JB, Abner EL, Jicha GA, Kapogiannis D. High complement levels in astrocyte-derived exosomes of Alzheimer disease. Ann Neurol 2018; 83 (03) 544-552
- 59 Goetzl EJ, Mustapic M, Kapogiannis D. et al. Cargo proteins of plasma astrocyte-derived exosomes in Alzheimer's disease. FASEB J 2016; 30 (11) 3853-3859 DOI: 10.1096/fj.201600756R.
- 60 Pant S, Hilton H, Burczynski ME. The multifaceted exosome: biogenesis, role in normal and aberrant cellular function, and frontiers for pharmacological and biomarker opportunities. Biochem Pharmacol 2012; 83 (11) 1484-1494
- 61 Burgos K, Malenica I, Metpally R. et al. Profiles of extracellular miRNA in cerebrospinal fluid and serum from patients with Alzheimer's and Parkinson's diseases correlate with disease status and features of pathology. PLoS One 2014; 9 (05) e94839
- 62 Liu CG, Song J, Zhang YQ, Wang PC. MicroRNA-193b is a regulator of amyloid precursor protein in the blood and cerebrospinal fluid derived exosomal microRNA-193b is a biomarker of Alzheimer's disease. Mol Med Rep 2014; 10 (05) 2395-2400
- 63 Cheng L, Doecke JD, Sharples RA. et al; Australian Imaging, Biomarkers and Lifestyle (AIBL) Research Group. Prognostic serum miRNA biomarkers associated with Alzheimer's disease shows concordance with neuropsychological and neuroimaging assessment. Mol Psychiatry 2015; 20 (10) 1188-1196
- 64 Yang TT, Liu CG, Gao SC, Zhang Y, Wang PC. The Serum Exosome Derived MicroRNA-135a, -193b, and -384 Were Potential Alzheimer's Disease Biomarkers. Biomed Environ Sci 2018; 31 (02) 87-96
- 65 Rani A, O'Shea A, Ianov L, Cohen RA, Woods AJ, Foster TC. miRNA in circulating microvesicles as biomarkers for age-related cognitive decline. Front Aging Neurosci 2017; 9: 323
- 66 Fitz NF, Wang J, Kamboh MI, Koldamova R, Lefterov I. Small nucleolar RNAs in plasma extracellular vesicles and their discriminatory power as diagnostic biomarkers of Alzheimer's disease. Neurobiol Dis 2021; 159: 105481 DOI: 10.1016/j.nbd.2021.105481.
- 67 Cavaillé J. Box C/D small nucleolar RNA genes and the Prader-Willi syndrome: a complex interplay. Wiley Interdiscip Rev RNA 2017; 8 (04) Epub2017Mar13. DOI: 10.1002/wrna.1417.
- 68 Chung MS, Langouët M, Chamberlain SJ, Carmichael GG. Prader-Willi syndrome: reflections on seminal studies and future therapies. Open Biol 2020; 10 (09) 200195 DOI: 10.1098/rsob.200195.
- 69 Driedonks TAP, van der Grein SG, Ariyurek Y. et al. Immune stimuli shape the small non-coding transcriptome of extracellular vesicles released by dendritic cells. Cell Mol Life Sci 2018; 75 (20) 3857-3875 DOI: 10.1007/s00018-018-2842-8.
- 70 Irimie AI, Zimta AA, Ciocan C. et al. The Unforeseen Non-Coding RNAs in Head and Neck Cancer. Genes (Basel) 2018; 9 (03) 134 DOI: 10.3390/genes9030134.
- 71 Lässer C, Shelke GV, Yeri A. et al. Two distinct extracellular RNA signatures released by a single cell type identified by microarray and next-generation sequencing. RNA Biol 2017; 14 (01) 58-72 DOI: 10.1080/15476286.2016.1249092.
- 72 Kim KM, Meng Q, Perez de Acha O. et al. Mitochondrial RNA in Alzheimer's Disease Circulating Extracellular Vesicles. Front Cell Dev Biol 2020; 8: 581882 DOI: 10.3389/fcell.2020.581882.
- 73 Beal MF. Mitochondrial dysfunction in neurodegenerative diseases. Biochim Biophys Acta 1998; 1366 (1-2): 211-223 DOI: 10.1016/s0005-2728(98)00114-5.
- 74 Beal MF. Oxidative damage as an early marker of Alzheimer's disease and mild cognitive impairment. Neurobiol Aging 2005; 26 (05) 585-586 DOI: 10.1016/j.neurobiolaging.2004.09.022.
- 75 Su H, Rustam YH, Masters CL. et al. Characterization of brain-derived extracellular vesicle lipids in Alzheimer's disease. J Extracell Vesicles 2021; 10 (07) e12089 DOI: 10.1002/jev2.12089.