Tissue Plasminogen Activator in Central Nervous System Physiology and Pathology: From Synaptic Plasticity to Alzheimer's Disease

Abstract

Tissue plasminogen activator's (tPA) fibrinolytic function in the vasculature is well-established. This specific role for tPA in the vasculature, however, contrasts with its pleiotropic activities in the central nervous system. Numerous physiological and pathological functions have been attributed to tPA in the central nervous system, including neurite outgrowth and regeneration; synaptic and spine plasticity; neurovascular coupling; neurodegeneration; microglial activation; and blood–brain barrier permeability. In addition, multiple substrates, both plasminogen-dependent and -independent, have been proposed to be responsible for tPA's action(s) in the central nervous system. This review aims to dissect a subset of these different functions and the different molecular mechanisms attributed to tPA in the context of learning and memory. We start from the original research that identified tPA as an immediate-early gene with a putative role in synaptic plasticity to what is currently known about tPA's role in a learning and memory disorder, Alzheimer's disease. We specifically focus on studies demonstrating tPA's involvement in the clearance of amyloid-β and neurovascular coupling. In addition, given that tPA has been shown to regulate blood–brain barrier permeability, which is perturbed in Alzheimer's disease, this review also discusses tPA-mediated vascular dysfunction and possible alternative mechanisms of action for tPA in Alzheimer's disease pathology.

Keywords

tissue plasminogen activator - Alzheimer's disease - learning and memory - vascular dysfunction - plasminogen activator inhibitor-1

Publication History

Article published online:
23 December 2021

• References

• 1 Qian Z, Gilbert ME, Colicos MA, Kandel ER, Kuhl D. Tissue-plasminogen activator is induced as an immediate-early gene during seizure, kindling and long-term potentiation. Nature 1993; 361 (6411): 453-457
• 2 Seeds NW, Williams BL, Bickford PC. Tissue plasminogen activator induction in Purkinje neurons after cerebellar motor learning. Science 1995; 270 (5244): 1992-1994
• 3 Tsirka SE, Gualandris A, Amaral DG, Strickland S. Excitotoxin-induced neuronal degeneration and seizure are mediated by tissue plasminogen activator. Nature 1995; 377 (6547): 340-344
• 4 Chen ZL, Strickland S. Neuronal death in the hippocampus is promoted by plasmin-catalyzed degradation of laminin. Cell 1997; 91 (07) 917-925
• 5 Su EJ, Fredriksson L, Geyer M. et al. Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke. Nat Med 2008; 14 (07) 731-737
• 6 Matys T, Strickland S. Tissue plasminogen activator and NMDA receptor cleavage. Nat Med 2003; 9 (04) 371-372 , author reply Nat Med 2003;9(04):372–373
• 7 Samson AL, Nevin ST, Croucher D. et al. Tissue-type plasminogen activator requires a co-receptor to enhance NMDA receptor function. J Neurochem 2008; 107 (04) 1091-1101
• 8 Pang PT, Teng HK, Zaitsev E. et al. Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science 2004; 306 (5695): 487-491
• 9 Polanco JC, Li C, Bodea LG, Martinez-Marmol R, Meunier FA, Götz J. Amyloid-β and tau complexity - towards improved biomarkers and targeted therapies. Nat Rev Neurol 2018; 14 (01) 22-39
• 10 Strickland S. Blood will out: vascular contributions to Alzheimer's disease. J Clin Invest 2018; 128 (02) 556-563
• 11 Ding J, Davis-Plourde KL, Sedaghat S. et al. Antihypertensive medications and risk for incident dementia and Alzheimer's disease: a meta-analysis of individual participant data from prospective cohort studies. Lancet Neurol 2020; 19 (01) 61-70
• 12 Ryu JK, Rafalski VA, Meyer-Franke A. et al. Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration. Nat Immunol 2018; 19 (11) 1212-1223
• 13 Frey U, Müller M, Kuhl D. A different form of long-lasting potentiation revealed in tissue plasminogen activator mutant mice. J Neurosci 1996; 16 (06) 2057-2063
• 14 Calabresi P, Napolitano M, Centonze D. et al. Tissue plasminogen activator controls multiple forms of synaptic plasticity and memory. Eur J Neurosci 2000; 12 (03) 1002-1012
• 15 Huang YY, Bach ME, Lipp HP. 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 U S A 1996; 93 (16) 8699-8704
• 16 Zhuo M, Holtzman DM, Li Y. et al. Role of tissue plasminogen activator receptor LRP in hippocampal long-term potentiation. J Neurosci 2000; 20 (02) 542-549
• 17 Wu F, Torre E, Cuellar-Giraldo D. et al. Tissue-type plasminogen activator triggers the synaptic vesicle cycle in cerebral cortical neurons. J Cereb Blood Flow Metab 2015; 35 (12) 1966-1976
• 18 Diaz A, Jeanneret V, Merino P, McCann P, Yepes M. Tissue-type plasminogen activator regulates p35-mediated Cdk5 activation in the postsynaptic terminal. J Cell Sci 2019; 132 (05) jcs224196
• 19 Jeanneret V, Wu F, Merino P. et al. Tissue-type plasminogen activator (tPA) modulates the postsynaptic response of cerebral cortical neurons to the presynaptic release of glutamate. Front Mol Neurosci 2016; 9: 121
• 20 Chater TE, Goda Y. The role of AMPA receptors in postsynaptic mechanisms of synaptic plasticity. Front Cell Neurosci 2014; 8: 401
• 21 Bianchetta MJ, Lam TT, Jones SN, Morabito MA. Cyclin-dependent kinase 5 regulates PSD-95 ubiquitination in neurons. J Neurosci 2011; 31 (33) 12029-12035
• 22 Baranes D, Lederfein D, Huang YY, Chen M, Bailey CH, Kandel ER. Tissue plasminogen activator contributes to the late phase of LTP and to synaptic growth in the hippocampal mossy fiber pathway. Neuron 1998; 21 (04) 813-825
• 23 Madani R, Hulo S, Toni N. et al. Enhanced hippocampal long-term potentiation and learning by increased neuronal expression of tissue-type plasminogen activator in transgenic mice. EMBO J 1999; 18 (11) 3007-3012
• 24 Medcalf RL, Rüegg M, Schleuning WD. A DNA motif related to the cAMP-responsive element and an exon-located activator protein-2 binding site in the human tissue-type plasminogen activator gene promoter cooperate in basal expression and convey activation by phorbol ester and cAMP. J Biol Chem 1990; 265 (24) 14618-14626
• 25 Abel T, Nguyen PV, Barad M, Deuel TA, Kandel ER, Bourtchouladze R. Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory. Cell 1997; 88 (05) 615-626
• 26 Hu K, Yang J, Tanaka S, Gonias SL, Mars WM, Liu Y. Tissue-type plasminogen activator acts as a cytokine that triggers intracellular signal transduction and induces matrix metalloproteinase-9 gene expression. J Biol Chem 2006; 281 (04) 2120-2127
• 27 Korte M, Carroll P, Wolf E, Brem G, Thoenen H, Bonhoeffer T. Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. Proc Natl Acad Sci U S A 1995; 92 (19) 8856-8860
• 28 Korte M, Kang H, Bonhoeffer T, Schuman E. A role for BDNF in the late-phase of hippocampal long-term potentiation. Neuropharmacology 1998; 37 (4-5): 553-559
• 29 Minichiello L, Calella AM, Medina DL, Bonhoeffer T, Klein R, Korte M. Mechanism of TrkB-mediated hippocampal long-term potentiation. Neuron 2002; 36 (01) 121-137
• 30 Xu B, Gottschalk W, Chow A. et al. The role of brain-derived neurotrophic factor receptors in the mature hippocampus: modulation of long-term potentiation through a presynaptic mechanism involving TrkB. J Neurosci 2000; 20 (18) 6888-6897
• 31 Lee R, Kermani P, Teng KK, Hempstead BL. Regulation of cell survival by secreted proneurotrophins. Science 2001; 294 (5548): 1945-1948
• 32 Scalettar BA, Jacobs C, Fulwiler A. et al. Hindered submicron mobility and long-term storage of presynaptic dense-core granules revealed by single-particle tracking. Dev Neurobiol 2012; 72 (09) 1181-1195
• 33 Conner JM, Lauterborn JC, Yan Q, Gall CM, Varon S. Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNS: evidence for anterograde axonal transport. J Neurosci 1997; 17 (07) 2295-2313
• 34 Yan Q, Rosenfeld RD, Matheson CR. et al. Expression of brain-derived neurotrophic factor protein in the adult rat central nervous system. Neuroscience 1997; 78 (02) 431-448
• 35 Danzer SC, McNamara JO. Localization of brain-derived neurotrophic factor to distinct terminals of mossy fiber axons implies regulation of both excitation and feedforward inhibition of CA3 pyramidal cells. J Neurosci 2004; 24 (50) 11346-11355
• 36 Stevenson TK, Lawrence DA. Characterization of tissue plasminogen activator expression and trafficking in the adult murine brain. eNeuro 2018;5(04):ENEURO.0119-18.2018
• 37 Rollenhagen A, Lübke JH. The mossy fiber bouton: the “common” or the “unique” synapse?. Front Synaptic Neurosci 2010; 2: 2
• 38 Acsády L, Kamondi A, Sík A, Freund T, Buzsáki G. GABAergic cells are the major postsynaptic targets of mossy fibers in the rat hippocampus. J Neurosci 1998; 18 (09) 3386-3403
• 39 Pawlak R, Nagai N, Urano T. et al. Rapid, specific and active site-catalyzed effect of tissue-plasminogen activator on hippocampus-dependent learning in mice. Neuroscience 2002; 113 (04) 995-1001
• 40 Rodriguiz RM, Wetsel WC. Assessments of Cognitive Deficits in Mutant Mice. In: Levin ED, Buccafusco JJ. eds. Animal Models of Cognitive Impairment. 2006 Boca Raton, FL: CRC Press/Taylor & Francis;
• 41 Kim EJ, Pellman B, Kim JJ. Stress effects on the hippocampus: a critical review. Learn Mem 2015; 22 (09) 411-416
• 42 Pawlak R, Magarinos AM, Melchor J, McEwen B, Strickland S. Tissue plasminogen activator in the amygdala is critical for stress-induced anxiety-like behavior. Nat Neurosci 2003; 6 (02) 168-174
• 43 Matys T, Pawlak R, Matys E, Pavlides C, McEwen BS, Strickland S. Tissue plasminogen activator promotes the effects of corticotropin-releasing factor on the amygdala and anxiety-like behavior. Proc Natl Acad Sci U S A 2004; 101 (46) 16345-16350
• 44 Thomas GM, Huganir RL. MAPK cascade signalling and synaptic plasticity. Nat Rev Neurosci 2004; 5 (03) 173-183
• 45 Bennur S, Shankaranarayana Rao BS, Pawlak R, Strickland S, McEwen BS, Chattarji S. Stress-induced spine loss in the medial amygdala is mediated by tissue-plasminogen activator. Neuroscience 2007; 144 (01) 8-16
• 46 Rodriguez G, Moore SJ, Neff RC. et al. Deficits across multiple behavioral domains align with susceptibility to stress in 129S1/SvImJ mice. Neurobiol Stress 2020; 13: 100262
• 47 Moore SJ, Deshpande K, Stinnett GS, Seasholtz AF, Murphy GG. Conversion of short-term to long-term memory in the novel object recognition paradigm. Neurobiol Learn Mem 2013; 105: 174-185
• 48 Jacobsen JS, Comery TA, Martone RL. et al. Enhanced clearance of Abeta in brain by sustaining the plasmin proteolysis cascade. Proc Natl Acad Sci U S A 2008; 105 (25) 8754-8759
• 49 Van Nostrand WE, Porter M. Plasmin cleavage of the amyloid beta-protein: alteration of secondary structure and stimulation of tissue plasminogen activator activity. Biochemistry 1999; 38 (35) 11570-11576
• 50 Ledesma MD, Da Silva JS, Crassaerts K, Delacourte A, De Strooper B, Dotti CG. Brain plasmin enhances APP alpha-cleavage and Abeta degradation and is reduced in Alzheimer's disease brains. EMBO Rep 2000; 1 (06) 530-535
• 51 Tucker HM, Kihiko M, Caldwell JN. et al. The plasmin system is induced by and degrades amyloid-beta aggregates. J Neurosci 2000; 20 (11) 3937-3946
• 52 Tucker HM, Kihiko-Ehmann M, Wright S, Rydel RE, Estus S. Tissue plasminogen activator requires plasminogen to modulate amyloid-beta neurotoxicity and deposition. J Neurochem 2000; 75 (05) 2172-2177
• 53 Melchor JP, Pawlak R, Strickland S. The tissue plasminogen activator-plasminogen proteolytic cascade accelerates amyloid-beta (Abeta) degradation and inhibits Abeta-induced neurodegeneration. J Neurosci 2003; 23 (26) 8867-8871
• 54 Liu RM, van Groen T, Katre A. et al. Knockout of plasminogen activator inhibitor 1 gene reduces amyloid beta peptide burden in a mouse model of Alzheimer's disease. Neurobiol Aging 2011; 32 (06) 1079-1089
• 55 Oh SB, Byun CJ, Yun JH. et al. Tissue plasminogen activator arrests Alzheimer's disease pathogenesis. Neurobiol Aging 2014; 35 (03) 511-519
• 56 Tarasoff-Conway JM, Carare RO, Osorio RS. et al. Clearance systems in the brain-implications for Alzheimer disease. Nat Rev Neurol 2015; 11 (08) 457-470
• 57 Kingston IB, Castro MJ, Anderson S. In vitro stimulation of tissue-type plasminogen activator by Alzheimer amyloid beta-peptide analogues. Nat Med 1995; 1 (02) 138-142
• 58 Wnendt S, Wetzels I, Günzler WA. Amyloid beta peptides stimulate tissue-type plasminogen activator but not recombinant prourokinase. Thromb Res 1997; 85 (03) 217-224
• 59 Kranenburg O, Bouma B, Kroon-Batenburg LM. et al. Tissue-type plasminogen activator is a multiligand cross-beta structure receptor. Curr Biol 2002; 12 (21) 1833-1839
• 60 Kruithof EK, Schleuning WD. A comparative study of amyloid-beta (1-42) as a cofactor for plasminogen activation by vampire bat plasminogen activator and recombinant human tissue-type plasminogen activator. Thromb Haemost 2004; 92 (03) 559-567
• 61 Rebeck GW, Harr SD, Strickland DK, Hyman BT. Multiple, diverse senile plaque-associated proteins are ligands of an apolipoprotein E receptor, the alpha 2-macroglobulin receptor/low-density-lipoprotein receptor-related protein. Ann Neurol 1995; 37 (02) 211-217
• 62 Qiu Z, Strickland DK, Hyman BT, Rebeck GW. Alpha2-macroglobulin enhances the clearance of endogenous soluble beta-amyloid peptide via low-density lipoprotein receptor-related protein in cortical neurons. J Neurochem 1999; 73 (04) 1393-1398
• 63 Bu G, Maksymovitch EA, Nerbonne JM, Schwartz AL. Expression and function of the low density lipoprotein receptor-related protein (LRP) in mammalian central neurons. J Biol Chem 1994; 269 (28) 18521-18528
• 64 Yang L, Liu CC, Zheng H. et al. LRP1 modulates the microglial immune response via regulation of JNK and NF-κB signaling pathways. J Neuroinflammation 2016; 13 (01) 304
• 65 Liu CC, Hu J, Zhao N. et al. Astrocytic LRP1 mediates brain Aβ clearance and impacts amyloid deposition. J Neurosci 2017; 37 (15) 4023-4031
• 66 Storck SE, Meister S, Nahrath J. et al. Endothelial LRP1 transports amyloid-β(1-42) across the blood-brain barrier. J Clin Invest 2016; 126 (01) 123-136
• 67 Kanekiyo T, Liu CC, Shinohara M, Li J, Bu G. LRP1 in brain vascular smooth muscle cells mediates local clearance of Alzheimer's amyloid-β. J Neurosci 2012; 32 (46) 16458-16465
• 68 Kanekiyo T, Cirrito JR, Liu CC. et al. Neuronal clearance of amyloid-β by endocytic receptor LRP1. J Neurosci 2013; 33 (49) 19276-19283
• 69 Ma Q, Zhao Z, Sagare AP. et al. Blood-brain barrier-associated pericytes internalize and clear aggregated amyloid-β42 by LRP1-dependent apolipoprotein E isoform-specific mechanism. Mol Neurodegener 2018; 13 (01) 57
• 70 Fujiyoshi M, Tachikawa M, Ohtsuki S. et al. Amyloid-β peptide(1-40) elimination from cerebrospinal fluid involves low-density lipoprotein receptor-related protein 1 at the blood-cerebrospinal fluid barrier. J Neurochem 2011; 118 (03) 407-415
• 71 Yamamoto K, Takeshita K, Saito H. Plasminogen activator inhibitor-1 in aging. Semin Thromb Hemost 2014; 40 (06) 652-659
• 72 Cacquevel M, Launay S, Castel H. et al. Ageing and amyloid-beta peptide deposition contribute to an impaired brain tissue plasminogen activator activity by different mechanisms. Neurobiol Dis 2007; 27 (02) 164-173
• 73 Bennett RE, Robbins AB, Hu M. et al. Tau induces blood vessel abnormalities and angiogenesis-related gene expression in P301L transgenic mice and human Alzheimer's disease. Proc Natl Acad Sci U S A 2018; 115 (06) E1289-E1298
• 74 Newcombe EA, Camats-Perna J, Silva ML, Valmas N, Huat TJ, Medeiros R. Inflammation: the link between comorbidities, genetics, and Alzheimer's disease. J Neuroinflammation 2018; 15 (01) 276
• 75 Killin LO, Starr JM, Shiue IJ, Russ TC. Environmental risk factors for dementia: a systematic review. BMC Geriatr 2016; 16 (01) 175
• 76 Van Cauwenberghe C, Van Broeckhoven C, Sleegers K. The genetic landscape of Alzheimer disease: clinical implications and perspectives. Genet Med 2016; 18 (05) 421-430
• 77 Gerenu G, Martisova E, Ferrero H. et al. 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 (04) 991-1001
• 78 Akhter H, Huang WT, van Groen T, Kuo HC, Miyata T, Liu RM. A small molecule inhibitor of plasminogen activator inhibitor-1 reduces brain amyloid-β load and improves memory in an animal model of Alzheimer's disease. J Alzheimers Dis 2018; 64 (02) 447-457
• 79 Park L, Zhou J, Koizumi K. et al. tPA deficiency underlies neurovascular coupling dysfunction by amyloid-β. J Neurosci 2020; 40 (42) 8160-8173
• 80 Lopez SA, Flagel SB. A proposed role for glucocorticoids in mediating dopamine-dependent cue-reward learning. Stress 2021; 24 (02) 154-167
• 81 Daviu N, Bruchas MR, Moghaddam B, Sandi C, Beyeler A. Neurobiological links between stress and anxiety. Neurobiol Stress 2019; 11: 100191
• 82 Makin S. The amyloid hypothesis on trial. Nature 2018; 559 (7715): S4-S7
• 83 Oxford AE, Stewart ES, Rohn TT. Clinical trials in Alzheimer's disease: a hurdle in the path of remedy. Int J Alzheimers Dis 2020; 2020: 5380346
• 84 Mullard A. Controversial Alzheimer's drug approval could affect other diseases. Nature 2021; 595 (7866): 162-163
• 85 Viana da Silva S, Zhang P, Haberl MG. et al. Hippocampal mossy fibers synapses in ca3 pyramidal cells are altered at an early stage in a mouse model of Alzheimer's disease. J Neurosci 2019; 39 (21) 4193-4205
• 86 Wilke SA, Raam T, Antonios JK. et al. Specific disruption of hippocampal mossy fiber synapses in a mouse model of familial Alzheimer's disease. PLoS One 2014; 9 (01) e84349
• 87 Sperling R. Functional MRI studies of associative encoding in normal aging, mild cognitive impairment, and Alzheimer's disease. Ann N Y Acad Sci 2007; 1097: 146-155
• 88 Yassa MA, Stark SM, Bakker A, Albert MS, Gallagher M, Stark CE. High-resolution structural and functional MRI of hippocampal CA3 and dentate gyrus in patients with amnestic mild cognitive impairment. Neuroimage 2010; 51 (03) 1242-1252
• 89 Setti SE, Hunsberger HC, Reed MN. Alterations in hippocampal activity and Alzheimer's disease. Transl Issues Psychol Sci 2017; 3 (04) 348-356
• 90 Kesner RP, Rolls ET. A computational theory of hippocampal function, and tests of the theory: new developments. Neurosci Biobehav Rev 2015; 48: 92-147
• 91 Gallagher M, Koh MT. Episodic memory on the path to Alzheimer's disease. Curr Opin Neurobiol 2011; 21 (06) 929-934
• 92 Park L, Gallo EF, Anrather J. et al. Key role of tissue plasminogen activator in neurovascular coupling. Proc Natl Acad Sci U S A 2008; 105 (03) 1073-1078
• 93 Iturria-Medina Y, Sotero RC, Toussaint PJ, Mateos-Pérez JM, Evans AC. Alzheimer's Disease Neuroimaging Initiative. Early role of vascular dysregulation on late-onset Alzheimer's disease based on multifactorial data-driven analysis. Nat Commun 2016; 7: 11934
• 94 Snyder HM, Corriveau RA, Craft S. et al. Vascular contributions to cognitive impairment and dementia including Alzheimer's disease. Alzheimers Dement 2015; 11 (06) 710-717
• 95 Beach TG, Potter PE, Kuo YM. et al. Cholinergic deafferentation of the rabbit cortex: a new animal model of Abeta deposition. Neurosci Lett 2000; 283 (01) 9-12
• 96 Clifford PM, Siu G, Kosciuk M. et al. Alpha7 nicotinic acetylcholine receptor expression by vascular smooth muscle cells facilitates the deposition of Abeta peptides and promotes cerebrovascular amyloid angiopathy. Brain Res 2008; 1234: 158-171
• 97 Hamel E. Perivascular nerves and the regulation of cerebrovascular tone. J Appl Physiol (1985) 2006; 100 (03) 1059-1064
• 98 Thomas T, Thomas G, McLendon C, Sutton T, Mullan M. beta-Amyloid-mediated vasoactivity and vascular endothelial damage. Nature 1996; 380 (6570): 168-171
• 99 Grothe M, Heinsen H, Teipel SJ. Atrophy of the cholinergic basal forebrain over the adult age range and in early stages of Alzheimer's disease. Biol Psychiatry 2012; 71 (09) 805-813
• 100 Minai K, Matsumoto T, Horie H. et al. Bradykinin stimulates the release of tissue plasminogen activator in human coronary circulation: effects of angiotensin-converting enzyme inhibitors. J Am Coll Cardiol 2001; 37 (06) 1565-1570
• 101 Klöcking HP. Release of plasminogen activator by acetylcholine from the isolated perfused pig ear. Thromb Res 1979; 16 (1-2): 261-264
• 102 Parameshwaran K, Dhanasekaran M, Suppiramaniam V. Amyloid beta peptides and glutamatergic synaptic dysregulation. Exp Neurol 2008; 210 (01) 7-13
• 103 Goto Y, Niidome T, Akaike A, Kihara T, Sugimoto H. Amyloid beta-peptide preconditioning reduces glutamate-induced neurotoxicity by promoting endocytosis of NMDA receptor. Biochem Biophys Res Commun 2006; 351 (01) 259-265
• 104 Snyder EM, Nong Y, Almeida CG. et al. Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci 2005; 8 (08) 1051-1058
• 105 Bi H, Sze CI. N-methyl-D-aspartate receptor subunit NR2A and NR2B messenger RNA levels are altered in the hippocampus and entorhinal cortex in Alzheimer's disease. J Neurol Sci 2002; 200 (1-2): 11-18
• 106 Hynd MR, Scott HL, Dodd PR. Differential expression of N-methyl-D-aspartate receptor NR2 isoforms in Alzheimer's disease. J Neurochem 2004; 90 (04) 913-919
• 107 Anfray A, Drieu A, Hingot V. et al. Circulating tPA contributes to neurovascular coupling by a mechanism involving the endothelial NMDA receptors. J Cereb Blood Flow Metab 2020; 40 (10) 2038-2054
• 108 ElAli A, Bordeleau M, Thériault P, Filali M, Lampron A, Rivest S. Tissue-plasminogen activator attenuates Alzheimer's disease-related pathology development in APPswe/PS1 mice. Neuropsychopharmacology 2016; 41 (05) 1297-1307
• 109 Wang YF, Tsirka SE, Strickland S, Stieg PE, Soriano SG, Lipton SA. Tissue plasminogen activator (tPA) increases neuronal damage after focal cerebral ischemia in wild-type and tPA-deficient mice. Nat Med 1998; 4 (02) 228-231
• 110 Benchenane K, Berezowski V, Ali C. et al. Tissue-type plasminogen activator crosses the intact blood-brain barrier by low-density lipoprotein receptor-related protein-mediated transcytosis. Circulation 2005; 111 (17) 2241-2249
• 111 Wojtas AM, Kang SS, Olley BM. et al. Loss of clusterin shifts amyloid deposition to the cerebrovasculature via disruption of perivascular drainage pathways. Proc Natl Acad Sci U S A 2017; 114 (33) E6962-E6971
• 112 Carare RO, Bernardes-Silva M, Newman TA. et al. Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology. Neuropathol Appl Neurobiol 2008; 34 (02) 131-144
• 113 Schley D, Carare-Nnadi R, Please CP, Perry VH, Weller RO. Mechanisms to explain the reverse perivascular transport of solutes out of the brain. J Theor Biol 2006; 238 (04) 962-974
• 114 Aldea R, Weller RO, Wilcock DM, Carare RO, Richardson G. Cerebrovascular smooth muscle cells as the drivers of intramural periarterial drainage of the brain. Front Aging Neurosci 2019; 11: 1
• 115 Cai Z, Qiao PF, Wan CQ, Cai M, Zhou NK, Li Q. Role of blood-brain barrier in Alzheimer's disease. J Alzheimers Dis 2018; 63 (04) 1223-1234
• 116 Montagne A, Zhao Z, Zlokovic BV. Alzheimer's disease: a matter of blood-brain barrier dysfunction?. J Exp Med 2017; 214 (11) 3151-3169
• 117 Fredriksson L, Stevenson TK, Su EJ. et al. Identification of a neurovascular signaling pathway regulating seizures in mice. Ann Clin Transl Neurol 2015; 2 (07) 722-738
• 118 Zeitelhofer M, Adzemovic MZ, Moessinger C. et al. Blocking PDGF-CC signaling ameliorates multiple sclerosis-like neuroinflammation by inhibiting disruption of the blood-brain barrier. Sci Rep 2020; 10 (01) 22383
• 119 Lewandowski SA, Nilsson I, Fredriksson L. et al. Presymptomatic activation of the PDGF-CC pathway accelerates onset of ALS neurodegeneration. Acta Neuropathol 2016; 131 (03) 453-464
• 120 Su EJ, Fredriksson L, Kanzawa M. et al. Imatinib treatment reduces brain injury in a murine model of traumatic brain injury. Front Cell Neurosci 2015; 9: 385
• 121 Asahi M, Asahi K, Jung JC, del Zoppo GJ, Fini ME, Lo EH. Role for matrix metalloproteinase 9 after focal cerebral ischemia: effects of gene knockout and enzyme inhibition with BB-94. J Cereb Blood Flow Metab 2000; 20 (12) 1681-1689
• 122 Asahi M, Wang X, Mori T. et al. Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood-brain barrier and white matter components after cerebral ischemia. J Neurosci 2001; 21 (19) 7724-7732
• 123 Turner RJ, Sharp FR. Implications of MMP9 for Blood Brain Barrier Disruption and Hemorrhagic Transformation Following Ischemic Stroke. Front Cell Neurosci 2016; 10: 56
• 124 Yepes M, Sandkvist M, Moore EG, Bugge TH, Strickland DK, Lawrence DA. Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor-related protein. J Clin Invest 2003; 112 (10) 1533-1540
• 125 Justicia C, Panés J, Solé S. et al. Neutrophil infiltration increases matrix metalloproteinase-9 in the ischemic brain after occlusion/reperfusion of the middle cerebral artery in rats. J Cereb Blood Flow Metab 2003; 23 (12) 1430-1440
• 126 Gidday JM, Gasche YG, Copin JC. et al. Leukocyte-derived matrix metalloproteinase-9 mediates blood-brain barrier breakdown and is proinflammatory after transient focal cerebral ischemia. Am J Physiol Heart Circ Physiol 2005; 289 (02) H558-H568
• 127 Su EJ, Cao C, Fredriksson L. et al. Microglial-mediated PDGF-CC activation increases cerebrovascular permeability during ischemic stroke. Acta Neuropathol 2017; 134 (04) 585-604
• 128 Fredriksson L, Li H, Fieber C, Li X, Eriksson U. Tissue plasminogen activator is a potent activator of PDGF-CC. EMBO J 2004; 23 (19) 3793-3802
• 129 Cortes-Canteli M, Mattei L, Richards AT, Norris EH, Strickland S. Fibrin deposited in the Alzheimer's disease brain promotes neuronal degeneration. Neurobiol Aging 2015; 36 (02) 608-617
• 130 Cortes-Canteli M, Paul J, Norris EH. et al. Fibrinogen and beta-amyloid association alters thrombosis and fibrinolysis: a possible contributing factor to Alzheimer's disease. Neuron 2010; 66 (05) 695-709
• 131 Klohs J, Baltes C, Princz-Kranz F. et al. Contrast-enhanced magnetic resonance microangiography reveals remodeling of the cerebral microvasculature in transgenic ArcAβ mice. J Neurosci 2012; 32 (05) 1705-1713
• 132 Merlini M, Rafalski VA, Rios Coronado PE. et al. Fibrinogen induces microglia-mediated spine elimination and cognitive impairment in an Alzheimer's disease model. Neuron 2019; 101 (06) 1099-1108.e6 , e6
• 133 Adzemovic MV, Zeitelhofer M, Eriksson U, Olsson T, Nilsson I. Imatinib ameliorates neuroinflammation in a rat model of multiple sclerosis by enhancing blood-brain barrier integrity and by modulating the peripheral immune response. PLoS One 2013; 8 (02) e56586
• 134 Krystosek A, Seeds NW. Plasminogen activator release at the neuronal growth cone. Science 1981; 213 (4515): 1532-1534
• 135 Oakley H, Cole SL, Logan S. et al. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J Neurosci 2006; 26 (40) 10129-10140
• 136 Mucke L, Masliah E, Yu GQ. et al. High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 2000; 20 (11) 4050-4058
• 137 Jankowsky JL, Slunt HH, Ratovitski T, Jenkins NA, Copeland NG, Borchelt DR. Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomol Eng 2001; 17 (06) 157-165
• 138 Blanchard V, Moussaoui S, Czech C. et al. Time sequence of maturation of dystrophic neurites associated with Abeta deposits in APP/PS1 transgenic mice. Exp Neurol 2003; 184 (01) 247-263
• 139 Hsiao K, Chapman P, Nilsen S. et al. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 1996; 274 (5284): 99-102
• 140 Santacruz K, Lewis J, Spires T. et al. Tau suppression in a neurodegenerative mouse model improves memory function. Science 2005; 309 (5733): 476-481
• 141 Holcomb L, Gordon MN, McGowan E. et al. Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 1998; 4 (01) 97-100