Alzheimer's disease (AD) is a central nervous system (CNS) disease characterized by loss of memory, cognitive functions, and neurodegeneration. Plasmin is an enzyme degrading many plasma proteins. In the CNS, plasmin may reduce the accumulation of beta amyloid (Aβ) and have other actions relevant to AD pathophysiology. Brain plasmin synthesis is regulated by two enzymes: one activating, the tissue plasminogen activator (tPA), and the other inhibiting, the plasminogen activator inhibitor-1 (PAI-1). We investigated the levels of tPA and PAI-1 in serum from 40 AD and 40 amnestic mild cognitively impaired (aMCI) patients compared to 10 cognitively healthy controls. Moreover, we also examined the PAI-1/tPA ratio in these patient groups. Venous blood was collected and the PAI-1 and tPA serum concentrations were quantified using sandwich ELISAs. The results showed that PAI-1 levels increased in AD and aMCI patients. This increase negatively correlated with cognitive performance measured using the Mini-Mental Status Exam (MMSE). Similarly, the ratio between tPA and PAI-1 gradually increases in aMCI and AD patients. This study demonstrates that AD and aMCI patients have altered PAI-1 serum levels and PAI-1/tPA ratio. Since these enzymes are CNS regulators of plasmin, PAI-1 serum levels could be a marker reflecting cognitive decline in AD.

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

See more in PubMed

Lane C.A., Hardy J., Schott J.M. Alzheimer’s disease. Eur. J. Neurol. 2018;25:59–70. doi: 10.1111/ene.13439. PubMed DOI

Jagust W. Imaging the evolution and pathophysiology of Alzheimer disease. Nat. Rev. Neurosci. 2018;19:687–700. doi: 10.1038/s41583-018-0067-3. PubMed DOI PMC

Counts S.E., He B., Prout J.G., Michalski B., Farotti L., Fahnestock M., Mufson E.J. Cerebrospinal Fluid proNGF: A Putative Biomarker for Early Alzheimer’s Disease. Curr. Alzheimer Res. 2016;13:800–808. PubMed PMC

Yang T., Li S., Xu H., Walsh D.M., Selkoe D.J. Large Soluble Oligomers of Amyloid β-Protein from Alzheimer Brain Are Far Less Neuroactive Than the Smaller Oligomers to Which They Dissociate. J. Neurosci. 2016;37:152–163. doi: 10.1523/JNEUROSCI.1698-16.2016. PubMed DOI PMC

Alifragis P., Marsh J. Synaptic dysfunction in Alzheimer’s disease: The effects of amyloid beta on synaptic vesicle dynamics as a novel target for therapeutic intervention. Neural Regen. Res. 2018;13:616. doi: 10.4103/1673-5374.230276. 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;25:303–313. doi: 10.1111/cns.13082. PubMed DOI PMC

Miszta A., Huskens D., Donkervoort D., Roberts M.J.M., Wolberg A.S., de Laat B. Assessing Plasmin Generation in Health and Disease. Int. J. Mol. Sci. 2021;22:2758. doi: 10.3390/ijms22052758. PubMed DOI PMC

Rosso M. Del The plasminogen activation system in inflammation. Front. Biosci. 2008;13:4667. doi: 10.2741/3032. PubMed DOI

Barker R., Love S., Kehoe P.G. Plasminogen and plasmin in Alzheimer’s disease. Brain Res. 2010;1355:7–15. doi: 10.1016/j.brainres.2010.08.025. PubMed DOI

Ledesma M.D., Da Silva J.S., Crassaerts K., Delacourte A., De Strooper B., Dotti C.G. Brain plasmin enhances APP α-cleavage and Aβ degradation and is reduced in Alzheimer’s disease brains. EMBO Rep. 2000;1:530–535. doi: 10.1093/embo-reports/kvd107. PubMed DOI PMC

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;7:59–64. doi: 10.1038/83358. PubMed DOI

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;1863:991–1001. doi: 10.1016/j.bbadis.2017.01.023. PubMed DOI

Leal G., Bramham C.R., Duarte C.B. BDNF and Hippocampal Synaptic Plasticity. Vitam. Horm. 2017;104:153–195. PubMed

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

Ploplis V., Castellino F. Structure and function of the plasminogen/plasmin system. Thromb. Haemost. 2005;93:647–654. doi: 10.1160/TH04-12-0842. PubMed DOI

Salles F.J., Strickland S. Localization and regulation of the tissue plasminogen activator-plasmin system in the hippocampus. J. Neurosci. 2002;22:2125–2134. 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;32:48–55. doi: 10.1016/j.tins.2008.09.006. PubMed DOI

Barker R., Kehoe P.G., Love S. Activators and inhibitors of the plasminogen system in Alzheimer’s disease. J. Cell. Mol. Med. 2012;16:865–876. doi: 10.1111/j.1582-4934.2011.01394.x. PubMed DOI PMC

Ledesma M.D., Abad-Rodriguez J., Galvan C., Biondi E., Navarro P., Delacourte A., Dingwall C., Dotti C.G. Raft disorganization leads to reduced plasmin activity in Alzheimer’s disease brains. EMBO Rep. 2003;4:1190–1196. doi: 10.1038/sj.embor.7400021. PubMed DOI PMC

Jacobsen J.S., Comery T.A., Martone R.L., Elokdah H., Crandall D.L., Oganesian A., Aschmies S., Kirksey Y., Gonzales C., Xu J., et al. Enhanced clearance of A in brain by sustaining the plasmin proteolysis cascade. Proc. Natl. Acad. Sci. USA. 2008;105:8754–8759. doi: 10.1073/pnas.0710823105. PubMed DOI PMC

Tucker H.M., Kihiko M., Caldwell J.N., Wright S., Kawarabayashi T., Price D., Walker D., Scheff S., McGillis J.P., Rydel R.E., et al. The Plasmin System Is Induced by and Degrades Amyloid-β Aggregates. J. Neurosci. 2000;20:3937–3946. doi: 10.1523/JNEUROSCI.20-11-03937.2000. PubMed DOI PMC

Tucker H.M., Kihiko-Ehmann M., Wright S., Rydel R.E., Estus S. Tissue Plasminogen Activator Requires Plasminogen to Modulate Amyloid-β Neurotoxicity and Deposition. J. Neurochem. 2002;75:2172–2177. doi: 10.1046/j.1471-4159.2000.0752172.x. PubMed DOI

Oh J., Lee H.-J., Song J.-H., Park S.I., Kim H. Plasminogen activator inhibitor-1 as an early potential diagnostic marker for Alzheimer’s disease. Exp. Gerontol. 2014;60:87–91. doi: 10.1016/j.exger.2014.10.004. 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. Alzheimer’s Dis. 2018;63:835–845. doi: 10.3233/JAD-171038. PubMed DOI

Liu R.-M., van Groen T., Katre A., Cao D., Kadisha I., Ballinger C., Wang L., Carroll S.L., Li L. Knockout of plasminogen activator inhibitor 1 gene reduces amyloid beta peptide burden in a mouse model of Alzheimer’s disease. Neurobiol. Aging. 2011;32:1079–1089. doi: 10.1016/j.neurobiolaging.2009.06.003. PubMed DOI PMC

Buisson A., Nicole O., Docagne F., Sartelet H., Mackenzie E.T., Vivien D. Up-regulation of a serine protease inhibitor in astrocytes mediates the neuroprotective activity of transforming growth factor β1. FASEB J. 1998;12:1683–1691. doi: 10.1096/fasebj.12.15.1683. PubMed DOI

Cacquevel M., Launay S., Castel H., Benchenane K., Chéenne S., Buée L., Moons L., Delacourte A., Carmeliet P., Vivien D. Ageing and amyloid-beta peptide deposition contribute to an impaired brain tissue plasminogen activator activity by different mechanisms. Neurobiol. Dis. 2007;27:164–173. doi: 10.1016/j.nbd.2007.04.004. PubMed DOI

Melchor J.P., Pawlak R., Strickland S. The Tissue Plasminogen Activator-Plasminogen Proteolytic Cascade Accelerates Amyloid-β (Aβ) Degradation and Inhibits Aβ-Induced Neurodegeneration. J. Neurosci. 2003;23:8867–8871. doi: 10.1523/JNEUROSCI.23-26-08867.2003. PubMed DOI PMC

Sawdey M.S., Loskutoff D.J. Regulation of murine type 1 plasminogen activator inhibitor gene expression in vivo. Tissue specificity and induction by lipopolysaccharide, tumor necrosis factor-alpha, and transforming growth factor-beta. J. Clin. Investig. 1991;88:1346–1353. doi: 10.1172/JCI115440. PubMed DOI PMC

Podor T.J., Joshua P., Butcher M., Seiffert D., Loskutoff D., Gauldie J. Accumulation of Type 1 Plasminogen Activator Inhibitor and Vitronectin at Sites of Cellular Necrosis and Inflammation. Ann. N. Y. Acad. Sci. 1992;667:173–177. doi: 10.1111/j.1749-6632.1992.tb51609.x. PubMed DOI

Kosaka K., Iseki E., Hino H., Akiyama H., Kondo H., Kato M., Ikeda K. Immunohistochemical localization of plasminogen activator inhibitor-1 in rat and human brain tissues. Neurosci. Lett. 2002;297:105–108. doi: 10.1016/s0304-3940(00)01679-7. PubMed DOI

Oh S.B., Byun C.J., Yun J.-H., Jo D.-G., Carmeliet P., Koh J.-Y., Lee J.-Y. Tissue plasminogen activator arrests Alzheimer’s disease pathogenesis. Neurobiol. Aging. 2014;35:511–519. doi: 10.1016/j.neurobiolaging.2013.09.020. PubMed DOI

Bi Oh S., Suh N., Kim I., Lee J.-Y.Y. Impacts of aging and amyloid-β deposition on plasminogen activators and plasminogen activator inhibitor-1 in the Tg2576 mouse model of Alzheimer’s disease. Brain Res. 2015;1597:159–167. doi: 10.1016/j.brainres.2014.11.042. PubMed DOI

Fabbro S., Seeds N.W. Plasminogen activator activity is inhibited while neuroserpin is up-regulated in the Alzheimer disease brain. J. Neurochem. 2009;109:303–315. doi: 10.1111/j.1471-4159.2009.05894.x. PubMed DOI

Medina M.G., Ledesma M.D., Domínguez J.E., Medina M., Zafra D., Alameda F., Dotti C.G., Navarro P. Tissue plasminogen activator mediates amyloid-induced neurotoxicity via Erk1/2 activation. EMBO J. 2005;24:1706–1716. doi: 10.1038/sj.emboj.7600650. PubMed DOI PMC

Kanno Y. The Role of Fibrinolytic Regulators in Vascular Dysfunction of Systemic Sclerosis. Int. J. Mol. Sci. 2019;20:619. doi: 10.3390/ijms20030619. PubMed DOI PMC

Huang Y.Y., Bach M.E., Lipp H.P., Zhuo M., Wolfer D.P., Hawkins R.D., Schoonjans L., Kandel E.R., Godfraind J.M., Mulligan R., et al. Mice lacking the gene encoding tissue-type plasminogen activator show a selective interference with late-phase long-term potentiation in both Schaffer collateral and mossy fiber pathways. Proc. Natl. Acad. Sci. USA. 1996;93:8699–8704. doi: 10.1073/pnas.93.16.8699. PubMed DOI PMC

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

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:e030379. doi: 10.1136/bmjopen-2019-030379. PubMed DOI PMC

Albert M.S., DeKosky S.T., Dickson D., Dubois B., Feldman H.H., Fox N.C., Gamst A., Holtzman D.M., Jagust W.J., Petersen R.C., et al. 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. Alzheimers. Dement. 2011;7:270–279. doi: 10.1016/j.jalz.2011.03.008. PubMed DOI PMC

McKhann G.M., Knopman D.S., Chertkow H., Hyman B.T., Jack C.R., Kawas C.H., Klunk W.E., Koroshetz W.J., Manly J.J., Mayeux R., et al. 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. 2011;7:263–269. doi: 10.1016/j.jalz.2011.03.005. PubMed DOI PMC

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

Fazekas F., Chawluk J., Alavi A., Hurtig H., Zimmerman R. MR signal abnormalities at 1.5 T in Alzheimer’s dementia and normal aging. Am. J. Roentgenol. 1987;149:351–356. doi: 10.2214/ajr.149.2.351. PubMed DOI

Plasminogen activator inhibitor-1 serum levels in frontotemporal lobar degeneration

Serum PAI-1/BDNF Ratio Is Increased in Alzheimer's Disease and Correlates with Disease Severity