Plasma Levels of Tissue-Type Plasminogen Activator (tPA) in Normal Aging and Alzheimer's Disease: Links With Cognition, Brain Structure, Brain Function and Amyloid Burden

Overview

Journal Front Aging Neurosci

Specialty Geriatrics

Date 2022 Jun 24

PMID 35747448

Authors

Clemence Tomadesso

Sara Martinez de Lizarrondo

Carine Ali

Brigitte Landeau

Florence Mezenge

Audrey Perrotin

Vincent De La Sayette

Denis Vivien

Gael Chetelat

Affiliations

Soon will be listed here.

Abstract

Tissue-type plasminogen activator (tPA) is a protease known for its fibrinolytic action but is also involved in physiological and pathophysiological aging processes; including amyloid elimination and synaptic plasticity. The aim of the study was to investigate the role of tPA in cognitive and brain aging. Therefore, we assessed the links between tPA plasma concentration and cognition, structural MRI, FDG-PET and Flobetapir-PET neuroimaging in 155 cognitively unimpaired adults (CUA, aged 20-85 years old) and 32 patients with Alzheimer's disease (ALZ). A positive correlation was found between tPA and age in CUA ( < 0.001), with males showing higher tPA than females ( = 0.05). No significant difference was found between ALZ patients and cognitively unimpaired elders (CUE). Plasma tPA in CUA negatively correlated with global brain volume. No correlation was found with brain FDG metabolism or amyloid deposition. Age-related tPA changes were associated to changes in blood pressure, glycemia and body mass index. Within the ALZ patients, tPA didn't correlate with any cognitive or neuroimaging measures, but only with physiological measures. Altogether our study suggests that increased tPA plasma concentration with age is related to neuronal alterations and cardiovascular risk factors.

Citing Articles

Vascular Dysfunction in Alzheimer's Disease: Alterations in the Plasma Contact and Fibrinolytic Systems.

Badimon A, Torrente D, Norris E Int J Mol Sci. 2023; 24(8).

PMID: 37108211 PMC: 10138543. DOI: 10.3390/ijms24087046.

References

Hagnelius N, Boman K, Nilsson T . Fibrinolysis and von Willebrand factor in Alzheimer's disease and vascular dementia--a case-referent study. Thromb Res. 2009; 126(1):35-8. DOI: 10.1016/j.thromres.2009.10.001. View

Takada Y, Takada A . Plasma levels of t-PA free PAI-1 and a complex of t-PA with PAI-1 in human males and females at various ages. Thromb Res. 1989; 55(5):601-9. DOI: 10.1016/0049-3848(89)90392-7. View

Asselbergs F, Williams S, Hebert P, Coffey C, Hillege H, Navis G . Gender-specific correlations of plasminogen activator inhibitor-1 and tissue plasminogen activator levels with cardiovascular disease-related traits. J Thromb Haemost. 2006; 5(2):313-20. DOI: 10.1111/j.1538-7836.2007.02311.x. View

Whelan C, Mattsson N, Nagle M, Vijayaraghavan S, Hyde C, Janelidze S . Multiplex proteomics identifies novel CSF and plasma biomarkers of early Alzheimer's disease. Acta Neuropathol Commun. 2019; 7(1):169. PMC: 6836495. DOI: 10.1186/s40478-019-0795-2. View

Gebara O, Mittleman M, Sutherland P, Lipinska I, Matheney T, Xu P . Association between increased estrogen status and increased fibrinolytic potential in the Framingham Offspring Study. Circulation. 1995; 91(7):1952-8. DOI: 10.1161/01.cir.91.7.1952. View

Tucker H, Kihiko M, Caldwell J, Wright S, Kawarabayashi T, Price D . The plasmin system is induced by and degrades amyloid-beta aggregates. J Neurosci. 2000; 20(11):3937-46. PMC: 6772619. View

Zegura B, Guzic-Salobir B, Sebestjen M, Keber I . The effect of various menopausal hormone therapies on markers of inflammation, coagulation, fibrinolysis, lipids, and lipoproteins in healthy postmenopausal women. Menopause. 2006; 13(4):643-50. DOI: 10.1097/01.gme.0000198485.70703.7a. View

Jansen W, Ossenkoppele R, Knol D, Tijms B, Scheltens P, Verhey F . Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA. 2015; 313(19):1924-38. PMC: 4486209. DOI: 10.1001/jama.2015.4668. View

Jack Jr C, Bennett D, Blennow K, Carrillo M, Dunn B, Budd Haeberlein S . NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018; 14(4):535-562. PMC: 5958625. DOI: 10.1016/j.jalz.2018.02.018. View

10.

Lowe G, Danesh J, Lewington S, Walker M, Lennon L, Thomson A . Tissue plasminogen activator antigen and coronary heart disease. Prospective study and meta-analysis. Eur Heart J. 2004; 25(3):252-9. DOI: 10.1016/j.ehj.2003.11.004. View

11.

Ridker P, Vaughan D, Stampfer M, Manson J, Hennekens C . Endogenous tissue-type plasminogen activator and risk of myocardial infarction. Lancet. 1993; 341(8854):1165-8. DOI: 10.1016/0140-6736(93)90998-v. View

12.

Petersen R, Morris J . Mild cognitive impairment as a clinical entity and treatment target. Arch Neurol. 2005; 62(7):1160-3. DOI: 10.1001/archneur.62.7.1160. View

13.

Calabresi P, Napolitano M, Centonze D, Marfia G, Gubellini P, Teule M . Tissue plasminogen activator controls multiple forms of synaptic plasticity and memory. Eur J Neurosci. 2000; 12(3):1002-12. DOI: 10.1046/j.1460-9568.2000.00991.x. View

14.

Koike K, Iso H, Shimamoto T, Kudo M, Umemura U, Sato S . Plasma fibrinogen, tissue plasminogen activator, plasminogen activator inhibitor 1, and their related factors in three Japanese population samples. Environ Health Prev Med. 2011; 3(3):158-63. PMC: 2723365. DOI: 10.1007/BF02931707. View

15.

Tomadesso C, Perrotin A, Mutlu J, Mezenge F, Landeau B, Egret S . Brain structural, functional, and cognitive correlates of recent versus remote autobiographical memories in amnestic Mild Cognitive Impairment. Neuroimage Clin. 2015; 8:473-82. PMC: 4474362. DOI: 10.1016/j.nicl.2015.05.010. View

16.

La Joie R, Landeau B, Perrotin A, Bejanin A, Egret S, Pelerin A . Intrinsic connectivity identifies the hippocampus as a main crossroad between Alzheimer's and semantic dementia-targeted networks. Neuron. 2014; 81(6):1417-1428. DOI: 10.1016/j.neuron.2014.01.026. View

17.

Sepulveda C, Palomo I, Fuentes E . Primary and secondary haemostasis changes related to aging. Mech Ageing Dev. 2015; 150:46-54. DOI: 10.1016/j.mad.2015.08.006. View

18.

Tomadesso C, De La Sayette V, de Flores R, Bourgeat P, Villemagne V, Egret S . Neuropsychology and neuroimaging profiles of amyloid-positive versus amyloid-negative amnestic mild cognitive impairment patients. Alzheimers Dement (Amst). 2018; 10:269-277. PMC: 5956939. DOI: 10.1016/j.dadm.2018.02.008. View

19.

Kingston I, Castro M, Anderson S . In vitro stimulation of tissue-type plasminogen activator by Alzheimer amyloid beta-peptide analogues. Nat Med. 1995; 1(2):138-42. DOI: 10.1038/nm0295-138. View

20.

Louessard M, Lacroix A, Martineau M, Mondielli G, Montagne A, Lesept F . Tissue Plasminogen Activator Expression Is Restricted to Subsets of Excitatory Pyramidal Glutamatergic Neurons. Mol Neurobiol. 2015; 53(7):5000-12. DOI: 10.1007/s12035-015-9432-7. View