Dementia with Lewy bodies (DLB), Parkinson's disease (PD), and multiple system atrophy (MSA) are neurodegenerative disorders characterized by abnormal accumulation of α-synuclein. Plasmin is a serine protease with a role in various physiological processes, including tissue and synaptic remodeling, inflammation regulation, and modulation of neurotrophic factors. It has also been shown that plasmin is able to cleave extracellular α-synuclein in neuronal cell cultures. The plasminogen activator inhibitor-1 (PAI-1) and the tissue plasminogen activator (tPA) regulate the synthesis and activity of plasmin in the brain. We measured the serum levels of tPA and PAI-1 in 30 DLB, 10 PD, and 12 MSA patients and compared them to 10 adults (controls). tPA and PAI-1 serum protein concentrations were quantified by ELISA and compared across the groups. The findings demonstrated that PAI-1 serum levels were increased in DLB (p < 0.05), PD (p < 0.01), and MSA (p < 0.001) patients as compared to controls. In addition, MSA patients had higher PAI-1 serum levels (p < 0.01) as compared to DLB patients, showing the highest PAI-1 levels among all groups. No differences in tPA serum levels were found among groups. Our findings suggest an involvement of plasmin system in these synucleinopathies although there are some limitations due to the heterogeneity of our cohort of participants. Thus, these data must be seen as preliminary observations and further studies in larger and more homogenous cohorts are needed before drawing definitive conclusions.

International Clinical Research Centre St Anne's University Hospital Brno 602 00 Czech Republic

Memory Clinic Department of Neurology 2nd Faculty of Medicine Charles University and Motol University Hospital Prague 150 06 Czech Republic

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Agarwal K., Backler W., Bayram E., Bloom L., Boeve B. F., Cha J.-H., Denslow M., Ferman T. J., Galasko D., Galvin J. E., Gomperts S. N., Irizarry M. C., Kantarci K., Kaushik H., Kietlinski M., Koenig A., Leverenz J. B., McKeith I., McLean P. J., Montine T. J., Moose S. O., O’Brien J. T., Panier V., Ramanathan S., Ringel M. S., Scholz S. W., Small J., Sperling R. A., Taylor A., Taylor J.-P., Ward R. A., Witten L., Hyman B. T.. Lewy Body Dementia: Overcoming Barriers and Identifying Solutions. Alzheimer’s Dementia. 2024;20:2298–2308. doi: 10.1002/alz.13674. PubMed DOI PMC

McKeith I. G., Boeve B. F., Dickson D. W., Halliday G., Taylor J.-P., Weintraub D., Aarsland D., Galvin J., Attems J., Ballard C. G., Bayston A., Beach T. G., Blanc F., Bohnen N., Bonanni L., Bras J., Brundin P., Burn D., Chen-Plotkin A., Duda J. E., El-Agnaf O., Feldman H., Ferman T. J., Ffytche D., Fujishiro H., Galasko D., Goldman J. G., Gomperts S. N., Graff-Radford N. R., Honig L. S., Iranzo A., Kantarci K., Kaufer D., Kukull W., Lee V. M. Y., Leverenz J. B., Lewis S., Lippa C., Lunde A., Masellis M., Masliah E., McLean P., Mollenhauer B., Montine T. J., Moreno E., Mori E., Murray M., O’Brien J. T., Orimo S., Postuma R. B., Ramaswamy S., Ross O. A., Salmon D. P., Singleton A., Taylor A., Thomas A., Tiraboschi P., Toledo J. B., Trojanowski J. Q., Tsuang D., Walker Z., Yamada M., Kosaka K.. Diagnosis and Management of Dementia with Lewy Bodies: Fourth Consensus Report of the DLB Consortium. Neurology. 2017;89(1):88–100. doi: 10.1212/WNL.0000000000004058. PubMed DOI PMC

Kalia L. V., Lang A. E.. Parkinson’s Disease. Lancet. 2015;386(9996):896–912. doi: 10.1016/S0140-6736(14)61393-3. PubMed DOI

Poewe W., Stankovic I., Halliday G., Meissner W. G., Wenning G. K., Pellecchia M. T., Seppi K., Palma J.-A., Kaufmann H.. Multiple SystemAtrophy. Nat. Rev. Dis. Primers. 2022;8(1):56. doi: 10.1038/s41572-022-00382-6. PubMed DOI

Koga S., Sekiya H., Kondru N., Ross O. A., Dickson D. W.. Neuropathology and Molecular Diagnosis of Synucleinopathies. Mol. Neurodegener. 2021;16(1):83. doi: 10.1186/s13024-021-00501-z. PubMed DOI PMC

Foubert-Samier A., Traon A. P.–L., Guillet F., Le-Goff M., Helmer C., Tison F., Rascol O., Proust-Lima C., Meissner W. G.. Disease Progression and Prognostic Factors in Multiple System Atrophy: A Prospective Cohort Study. Neurobiol. Dis. 2020;139:104813. doi: 10.1016/j.nbd.2020.104813. PubMed DOI

Estaun-Panzano J., Arotcarena M.-L., Bezard E.. Monitoring α-Synuclein Aggregation. Neurobiol. Dis. 2023;176:105966. doi: 10.1016/j.nbd.2022.105966. PubMed DOI PMC

Angelucci F., Čechová K., Průša R., Hort J.. Amyloid Beta Soluble Forms and Plasminogen Activation System in Alzheimer’s Disease: Consequences on Extracellular Maturation of Brain-Derived Neurotrophic Factor and Therapeutic Implications. CNS Neurosci. Ther. 2018;25(3):303–313. doi: 10.1111/cns.13082. PubMed DOI PMC

Centonze D., Napolitano M., Saulle E., Gubellini P., Picconi B., Martorana A., Pisani A., Gulino A., Bernardi G., Calabresi P.. Tissue Plasminogen Activator Is Required for Corticostriatal Long-Term Potentiation. Eur. J. Neurosci. 2002;16(4):713–721. doi: 10.1046/j.1460-9568.2002.02106.x. PubMed DOI

Calabresi P., Napolitano M., Centonze D., Marfia G. A., Gubellini P., Teule M. A., Berretta N., Bernardi G., Frati L., Tolu M., Gulino A.. Tissue Plasminogen Activator Controls Multiple Forms of Synaptic Plasticity and Memory. Eur. J. Neurosci. 2000;12(3):1002–1012. doi: 10.1046/j.1460-9568.2000.00991.x. PubMed DOI

Nicole O., Docagne F., Ali C., Margaill I., Carmeliet P., MacKenzie E. T., Vivien D., Buisson A.. The Proteolytic Activity of Tissue-Plasminogen Activator Enhances NMDA Receptor-Mediated Signaling. Nat. Med. 2001;7(1):59–64. doi: 10.1038/83358. PubMed DOI

Wiera G., Mozrzymas J. W.. Extracellular Proteolysis in Structural and Functional Plasticity of Mossy Fiber Synapses in Hippocampus. Front. Cell. Neurosci. 2015;9:427. doi: 10.3389/fncel.2015.00427. PubMed DOI PMC

Gerenu G., Martisova E., Ferrero H., Carracedo M., Rantamäki T., Ramirez M. J., Gil-Bea F. J.. Modulation of BDNF Cleavage by Plasminogen-Activator Inhibitor-1 Contributes to Alzheimer’s Neuropathology and Cognitive Deficits. Biochim. Biophys. Acta, Mol. Basis Dis. 2017;1863(4):991–1001. doi: 10.1016/j.bbadis.2017.01.023. PubMed DOI

Mossiat C., Prigent-Tessier A., Garnier P., Marie C., Jacquin A., Rodier M., Béjot Y., Prigent-Tessier A., Béjot Y., Jacquin A., Mossiat C., Marie C., Garnier P.. Exogenous T-PA Administration Increases Hippocampal Mature BDNF Levels. Plasmin- or NMDA-Dependent Mechanism? PLoS One. 2014;9(3):e92416. doi: 10.1371/journal.pone.0092416. PubMed DOI PMC

Castellino F. J., Castellino F.. Structure and Function of the Plasminogen/Plasmin System. Thromb. Haemostasis. 2005;93(04):647–654. doi: 10.1160/TH04-12-0842. PubMed DOI

Samson A. L., Medcalf R. L.. Tissue-Type Plasminogen Activator: A Multifaceted Modulator of Neurotransmission and Synaptic Plasticity. Neuron. 2006;50(5):673–678. doi: 10.1016/j.neuron.2006.04.013. PubMed DOI

Sallés F. J., Strickland S.. Localization and Regulation of the Tissue Plasminogen Activator-Plasmin System in the Hippocampus. J. Neurosci. 2002;22(6):2125–2134. doi: 10.1523/JNEUROSCI.22-06-02125.2002. PubMed DOI PMC

Yepes M., Roussel B. D., Ali C., Vivien D.. Tissue-Type Plasminogen Activator in the Ischemic Brain: More than a Thrombolytic. Trends Neurosci. 2009;32(1):48–55. doi: 10.1016/j.tins.2008.09.006. PubMed DOI

Kim K. S., Choi Y. R., Park J.-Y., Lee J.-H., Kim D. K., Lee S.-J., Paik S. R., Jou I., Park S. M.. Proteolytic Cleavage of Extracellular α-Synuclein by Plasmin. J. Biol. Chem. 2012;287(30):24862–24872. doi: 10.1074/jbc.M112.348128. PubMed DOI PMC

Park S. M., Kim K. S.. Proteolytic Clearance of Extracellular α-Synuclein as a New Therapeutic Approach against Parkinson Disease. Prion. 2013;7(2):121–126. doi: 10.4161/pri.22850. PubMed DOI PMC

Reuland C. J., Church F. C.. Synergy between Plasminogen Activator Inhibitor-1, α-Synuclein, and Neuroinflammation in Parkinson’s Disease. Med. Hypotheses. 2020;138:109602. doi: 10.1016/j.mehy.2020.109602. PubMed DOI

Speelman T., Dale L., Louw A., Verhoog N. J. D.. The Association of Acute Phase Proteins in Stress and Inflammation-Induced T2D. Cells. 2022;11(14):2163. doi: 10.3390/cells11142163. PubMed DOI PMC

Badran M., Gozal D.. PAI-1: A Major Player in the Vascular Dysfunction in Obstructive Sleep Apnea? Int. J. Mol. Sci. 2022;23(10):5516. doi: 10.3390/ijms23105516. PubMed DOI PMC

Dimova E. Y., Samoylenko A., Kietzmann T.. Oxidative Stress and Hypoxia: Implications for Plasminogen Activator Inhibitor-1 Expression. Antioxid. Redox Signaling. 2004;6(4):777–791. doi: 10.1089/1523086041361596. PubMed DOI

Hajer G. R., van Haeften T. W., Visseren F. L. J.. Adipose Tissue Dysfunction in Obesity, Diabetes, and Vascular Diseases. Eur. Heart J. 2008;29(24):2959–2971. doi: 10.1093/eurheartj/ehn387. PubMed DOI

Kim K. S., Choi Y. R., Park J.-Y., Lee J.-H., Kim D. K., Lee S.-J., Paik S. R., Jou I., Park S. M.. Proteolytic Cleavage of Extracellular α-Synuclein by Plasmin: Implications for Parkinson Disease. J. Biol. Chem. 2012;287(30):24862–24872. doi: 10.1074/jbc.M112.348128. PubMed DOI PMC

Zuccato C., Cattaneo E.. Brain-Derived Neurotrophic Factor in Neurodegenerative Diseases. Nat. Rev. Neurol. 2009;5(6):311–322. doi: 10.1038/nrneurol.2009.54. PubMed DOI

Scalzo P., Kümmer A., Bretas T. L., Cardoso F., Teixeira A. L.. Serum Levels of Brain-Derived Neurotrophic Factor Correlate with Motor Impairment in Parkinson’s Disease. J. Neurol. 2010;257(4):540–545. doi: 10.1007/s00415-009-5357-2. PubMed DOI

Wang J., Yuan Y., Cai R., Huang R., Tian S., Lin H., Guo D., Wang S.. Association between Plasma Levels of PAI-1, TPA/PAI-1 Molar Ratio, and Mild Cognitive Impairment in Chinese Patients with Type 2 Diabetes Mellitus. J. Alzheimers Dis. 2018;63(2):835–845. doi: 10.3233/JAD-171038. PubMed DOI

Guo C., Wang T., Zhang D., Ge X., Li J.. Plasminogen Decreases Aβ42 and Tau Deposition, and Shows Multi-Beneficial Effects on Alzheimer’s Disease in Mice and Humans. Biochem. Biophys. Res. Commun. 2023;654:102–111. doi: 10.1016/j.bbrc.2023.02.078. PubMed DOI

Guo C., Wang T., Huang H., Wang X., Jiang Y., Li J.. Plasminogen Degrades α-Synuclein, Tau and TDP-43 and Decreases Dopaminergic Neurodegeneration in Mouse Models of Parkinson’s Disease. Sci. Rep. 2024;14(1):8581. doi: 10.1038/s41598-024-59090-8. PubMed DOI PMC

Tanrikulu A. M., Ozdilek B., Agirbasli M.. Serum Levels of Plasminogen Activator Inhibitor-1 in Patients with Parkinson’s Disease. Med. Princ. Pract. 2024;33(6):562–568. doi: 10.1159/000540854. PubMed DOI PMC

Altalhi R., Pechlivani N., Ajjan R. A.. PAI-1 in Diabetes: Pathophysiology and Role as a Therapeutic Target. Int. J. Mol. Sci. 2021;22(6):3170. doi: 10.3390/ijms22063170. PubMed DOI PMC

Reuland C. J., Church F. C.. Synergy between Plasminogen Activator Inhibitor-1, α-Synuclein, and Neuroinflammation in Parkinson’s Disease. Med. Hypotheses. 2020;138:109602. doi: 10.1016/j.mehy.2020.109602. PubMed DOI

Poewe W., Stankovic I., Halliday G., Meissner W. G., Wenning G. K., Pellecchia M. T., Seppi K., Palma J.-A., Kaufmann H.. MultipleSystem Atrophy. Nat. Rev. Dis. Primers. 2022;8(1):56. doi: 10.1038/s41572-022-00382-6. PubMed DOI

Freuchet A., Pinçon A., Sette A., Arlehamn C. S. L.. Inflammation and Heterogeneity in Synucleinopathies. Front. Immunol. 2024;15:1432342. doi: 10.3389/fimmu.2024.1432342. PubMed DOI PMC

Rydbirk R., Østergaard O., Folke J., Hempel C., DellaValle B., Andresen T. L., Løkkegaard A., Hejl A.-M., Bode M., Blaabjerg M., Møller M., Danielsen E. H., Salvesen L., Starhof C. C., Bech S., Winge K., Rungby J., Pakkenberg B., Brudek T., Olsen J. V., Aznar S.. Brain Proteome Profiling Implicates the Complement and Coagulation Cascade in Multiple System Atrophy Brain Pathology. Cell. Mol. Life Sci. 2022;79(6):336. doi: 10.1007/s00018-022-04378-z. PubMed DOI PMC

Asi Y. T., Simpson J. E., Heath P. R., Wharton S. B., Lees A. J., Revesz T., Houlden H., Holton J. L.. Alpha-Synuclein MRNA Expression in Oligodendrocytes in MSA. Glia. 2014;62(6):964–970. doi: 10.1002/glia.22653. PubMed DOI PMC

Lin H., Tang R., Fan L., Wang E.. Exogenous Tetranectin Alleviates Pre-Formed-Fibrils-Induced Synucleinopathies in SH-SY5Y Cells by Activating the Plasminogen Activation System. Neurochem. Res. 2022;47(10):3192–3201. doi: 10.1007/s11064-022-03673-2. PubMed DOI

Rai S. N., Birla H., Singh S. S., Zahra W., Patil R. R., Jadhav J. P., Gedda M. R., Singh S. P.. Mucuna Pruriens Protects against MPTP Intoxicated Neuroinflammation in Parkinson’s Disease through NF-KB/PAKT Signaling Pathways. Front. Aging Neurosci. 2017;9:314845. doi: 10.3389/fnagi.2017.00421. PubMed DOI PMC

Rai S. N., Chaturvedi V. K., Singh P., Singh B. K., Singh M. P.. Mucuna Pruriens in Parkinson’s and in Some Other Diseases: Recent Advancement and Future Prospective. 3 Biotech. 2020;10(12):522. doi: 10.1007/s13205-020-02532-7. PubMed DOI PMC

Rai S. N., Yadav S. K., Singh D., Singh S. P.. Ursolic Acid Attenuates Oxidative Stress in Nigrostriatal Tissue and Improves Neurobehavioral Activity in MPTP-Induced Parkinsonian Mouse Model. J. Chem. Neuroanat. 2016;71:41–49. doi: 10.1016/j.jchemneu.2015.12.002. PubMed DOI

Sheardova K., Vyhnalek M., Nedelska Z., Laczo J., Andel R., Marciniak R., Cerman J., Lerch O H. J., Sheardova K., Vyhnalek M., Nedelska Z., Laczo J., Andel R., Marciniak R., Cerman J., Lerch O., Hort J.. Czech Brain Aging Study (CBAS): Prospective Multicentre Cohort Study on Risk and Protective Factors for Dementia in the Czech Republic. BMJ. Open. 2019;9(12):e030379. doi: 10.1136/bmjopen-2019-030379. PubMed DOI PMC

Yesavage J. A.. Geriatric Depression Scale. Psychopharmacol. Bull. 1988;24(4):709–711. PubMed

Wenning G. K., Stankovic I., Vignatelli L., Fanciulli A., Calandra-Buonaura G., Seppi K., Palma J., Meissner W. G., Krismer F., Berg D., Cortelli P., Freeman R., Halliday G., Höglinger G., Lang A., Ling H., Litvan I., Low P., Miki Y., Panicker J., Pellecchia M. T., Quinn N., Sakakibara R., Stamelou M., Tolosa E., Tsuji S., Warner T., Poewe W., Kaufmann H.. The Movement Disorder Society Criteria for the Diagnosis of Multiple System Atrophy. Mov. Disord. 2022;37(6):1131–1148. doi: 10.1002/mds.29005. PubMed DOI PMC

Postuma R. B., Berg D., Stern M., Poewe W., Olanow C. W., Oertel W., Obeso J., Marek K., Litvan I., Lang A. E., Halliday G., Goetz C. G., Gasser T., Dubois B., Chan P., Bloem B. R., Adler C. H., Deuschl G.. MDS Clinical Diagnostic Criteria for Parkinson’s Disease. Mov. Disord. 2015;30(12):1591–1601. doi: 10.1002/mds.26424. PubMed DOI

Movement Disorder Society Task Force on Rating Scales for Parkinson’s Disease. The Unified Parkinson’s Disease Rating Scale (UPDRS): Status and Recommendations. Mov. Disord. 2003;18(7):738–750. doi: 10.1002/mds.10473. PubMed DOI

Vassar S. D., Bordelon Y. M., Hays R. D., Diaz N., Rausch R., Mao C., Vickrey B. G.. Confirmatory Factor Analysis of the Motor Unified Parkinson’s Disease Rating Scale. Parkinson’s Dis. 2012;2012:719167. doi: 10.1155/2012/719167. PubMed DOI PMC

Angelucci F., Veverova K., Katonová A., Piendel L., Vyhnalek M., Hort J.. Alzheimer’s Disease Severity Is Associated with an Imbalance in Serum Levels of Enzymes Regulating Plasmin Synthesis. Pharmaceuticals. 2022;15(9):1074. doi: 10.3390/ph15091074. PubMed DOI PMC