Targeting thrombin: An inflammatory neurotoxin in alzheimer's disease

Journal of Alzheimer's Disease

Volumn 42, Issue , 2014, Pages S537-S544

  Grammas, Paula ^a,b,c   Martinez, Joseph M ^b  

^a Texas Alzheimer's Research and Care Consortium   (United States)

^b TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER   (United States)

^c TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER SCHOOL OF MEDICINE   (United States)

Author keywords

Alzheimer's disease; cardiovascular risk factors; cerebral microvasculature; cognitive decline; dabigatran; thrombin; thrombin inhibitors

Indexed keywords

NEUROTOXIN; THROMBIN; THROMBIN INHIBITOR; ANTITHROMBIN;

ALZHEIMER DISEASE; ASTROCYTE; BLOOD VESSEL INJURY; BRAIN; CARDIOVASCULAR RISK; CEREBROVASCULAR DISEASE; COGNITION; COGNITIVE DEFECT; DEGENERATIVE DISEASE; DIABETES MELLITUS; DRUG TARGETING; ENDOTHELIUM CELL; EPIDEMIC; HUMAN; HYPOXIA; MICROGLIA; MICROVASCULATURE; NERVOUS SYSTEM INFLAMMATION; NEUROTOXICITY; NONHUMAN; PATHOGENESIS; PROTEIN EXPRESSION; REVIEW; ANIMAL; COGNITION DISORDERS; COMPLICATION; DISEASE MODEL; DRUG EFFECTS; METABOLISM; MOUSE;

ALZHEIMER DISEASE; ANIMALS; ANTITHROMBINS; BRAIN; COGNITION DISORDERS; DISEASE MODELS, ANIMAL; HUMANS; MICE; THROMBIN;

EID: 84908202362     PISSN: 13872877     EISSN: 18758908     Source Type: Journal    
DOI: 10.3233/JAD-141557     Document Type: Review

References (88)

1. Prince M,Bryce R,Albanese E,Wimo A,Ribeiro W,Ferri CP 2013) The global prevalence of dementia: A systematic review and metaanalysis. Alzheimers Dement 9, 63-75.e62.
2. James B, Leurgans S, Hebert L, Scherr P, Yaffe K, Bennett D (2014) Contribution of Alzheimer disease to mortality in the United States. Neurology 82, 1045-1050.
3. Castellani RJ, Perry G (2012) Pathogeneisis and diseasemodifying therapy in Alzheimer's disease: The flat line of progress. Arch Med Res 43, 694-698.
4. Fraut schy S, Cole G (2010) Why pleiotropic interventions are needed for Alzheimer's disease. Mol Neurobiol 41, 392-409.
5. Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, Ki eburtz K, Raman R, Sun X, Aisen PS, Siemers E, Liu-Seifert H, Mohs R (2014) Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. N Engl JMed 370, 311-321.
6. Tolppanen A, Solomon A, Soininen H, Kivipelto M (2012) Midlife vascular risk factors and Alzheimer's disease: Evidence from epidemiological studies. J Alzheimers Dis 32, 531-540.
7. Justin B, Turek M, Hakim A (2013) Heart disease as a risk factor for dementia. Clin Epidemiol 5, 135-145.
8. Helzner EP, Luchsinger JA, Scarmeas N, Cosentino S, Brickman AM, Glym our MM, Stern Y (2009) Contribution of vascular risk factors to the progression in Alzheimer disease. Arch Neurol 66, 343-348.
9. Dickstein DL,Walsh J, Brautigam H, Stockton SD, Jr., Gandy S , Hof PR (2010) Role of vascular risk factors and vascular dysfunction in Alzheimer's disease. Mt Sinai J Med 77, 82-102.
10. Shah NS, Vidal JS, Masaki K, Petrovitch H, Ross GW, Tilley C , DeMattos RB, Tracy RP, White LR, Launer LJ (2012) Midlife blood pressure, plasma beta-Amyloid, and the risk for Alzheimer disease: The Honolulu Asia Aging Study. Hypertension 59, 780-786.
11. Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, BretelerMM(1999) Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology 53, 1937-1942.
12. Janson J, Laedtke T, Parisi JE, O'Brien P, Petersen RC, Butler PC (2004) Increased risk of type 2 diabetes in Alzheimer disease. Diabetes 53, 474-481.
13. Hofman A, Ott A, Breteler MM, Bots ML, Slo oter AJ, van Harskamp F, van Duijn CN, Van Broeckhoven C, Grobbee DE (1997) Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer's disease in the Rotterdam Study. Lancet 349, 151-154.
14. Daulatzai MA (2012) Quintessential risk factors: Their role in promoting cognitive dysfunction and Alzheimer's disease. Neurochem Res 37, 2627-2658.
15. Yaffe K, Vittinghoff E, Pletcher MJ, Hoang TD, Launer LJ, Whitmer R, Coker LH, Sidney S (2014) Early adult to midlife cardiovascular risk factors and cognitive function. Circulation 129, 1560-1567.
16. Nishtala A, Preis SR, Beiser A, Devine S, Hankee L, Seshadri S,Wolf PA, Au R (2014) Midlife cardiovascular risk impacts executive function: Framingham offspring study. Alzheimer Dis Assoc Disord 28, 16-22.
17. de la Torre JC (2012) Cerebral hemodynamics and vascular risk factors: Setting the stage for Alzheimer's disease. J Alzheimers Dis 32, 553-567.
18. Gudala K, Bansal D, Schifano F, Bhansali A (2013) Diabetes mellitus and risk of dementia: A meta-Analysis of prospective observational studies. J Diabetes Investig 4, 640-650.
19. Cheng G, Huang C, Deng H, Wang H (2012) Diabetes as a r isk factor for dementia and mild cognitive impairment: A meta-Analysis of longitudinal studies. Intern Med J 42, 484-491.
20. Tripathy D, Sanchez A, Yin X, Luo J, Martinez J, Grammas P (2013) Thrombin, amediator of cerebrovascular inflammation in AD and hypoxia. Front Aging Neurosci 5, 19.
21. Luo J, Martinez J, Yin X, Sanchez A, Tripathy D, Grammas P (2012) Hypoxia induces angiogenic factors in brain microvascular endothelial cells. Microvasc Res 83, 138-145.
22. ZlokovicBV(2002) Vascular disorder in Alzheimer's disease: Role in pathogenesis of dementia and therapeutic targets. Adv Drug Deliv Rev 54, 1553-1559.
23. Zlokovic BV (2008) The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57, 178-201.
24. Zhao WQ, Townsend M (2009) Insulin resistance and amyloidogenesis as common molecular foundation for type 2 diabetes and Alzheimer's disease. Biochim Biophys Acta 1792, 482-496.
25. Rojo LE, Fernandez JA, Maccioni AA, Jimenez JM,Maccioni RB (2008) Neuroinflammation: Implications for the pathogenesis and molecular diagnosis of Alzheimer's d isease. Arch Med Res 39, 1-16.
26. Rosenbaum MA, Miyazaki K, Graham LM (2012) Hypercholesterolemia and oxidative stress inhibit endothelial cell healing after arterial injury. J Vasc Surg 55, 489-496.
27. Singh VP, Bali A, Singh N, Jaggi AS (2014) Advanced glycation end products and diabetic complications. Korean J Physiol Pharmacol 18, 1-14.
28. IshibashiY, Matsui T, Ueda S, Fukami K,Yamagishi S (2014) Advanced glycation end products potentiate citrated plasmaevoked oxidative and inflammatory reactions in endothelial cells by up-regulating protease-Activated receptor-1 expression. Cardiovasc Diabetol 13, 60.
29. Li Z, Zhong Q, Yang T, Xie X, Chen M (2013) The role of profilin-1 in endothelial cell injury induced by advanced glycation end products (AGEs). Cardiovasc Diabetol 12, 141.
30. Yaffe K, Lindquist K, Schwartz AV, Vitartas C, Vittinghoff E, Satterfield S, Simonsick EM, Launer L, Rosano C, Cauley JA, Harris T (2011) Advanced glycation end product level, diabetes, and accelerated cognitive aging. Neurology 77, 1351-1356.
31. Ramachandran R (2012) Developing PAR1 antagonists: Minding the endothelial gap. Discov Med 13, 425-431.
32. Chapman J (2013) Coagulation i n inflammatory diseases of the central nervous system. Semin Thromb Hemost 39, 876-880.
33. Aoki I, Shimoyama K, Aoki N, Homori M, Yanagisawa A, Nakahara K, Kawai Y, Kitamura SI, Ishi kawa K (1996) Platelet-dependent thrombin generation in patients with diabetes mellitus: Effects of glycemic control on coagulability in diabetes. J Am Coll Cardiol 27, 560-566.
34. Grammas P, Ottman T, Reimann-Philipp U, Larabee J,Weigel PH (2004) Injured brain endothelial cells release neurotoxic thrombin. J Alzheimers Dis 6, 275-281.
35. Grammas P, Samany PG, Thirumangalakudi L (2006) Thrombin and inflammatory proteins are elevated in Alzheimer's disease microvessels: Implications for disease pathogenesis. J Alzheimers Dis 9, 51-58.
36. Yin X,W right J,Wall T, Grammas P (2010) Brain endothelial cells synthesize neurotoxic thrombin in Alzheimer's diease. Am J Pathol 176, 1600-1606.
37. Peers C, Dallas ML, Boycott HE, Scragg JL, Pearson HA, Boyle JP (2009) Hypoxia and neurodegeneration. Ann N Y Acad Sci 1177, 169-177.
38. Peers C, Pearson HA, Boyle JP (2007) Hypoxia and Alzheimer's disease. Essays Biochem 43, 153-164.
39. Honig LS, Tang MX, Albert S, Costa R, Luchsinger J, Manly J, Stern Y, Mayeux R (2003) Stroke and the risk of Alzheimer disease. Arch Neurol 60, 1707-1712.
40. Giordano FJ (2005) Oxygen, oxidative stress, hypoxia, and heart failure. J Clin Invest 115, 500-508.
41. Sanchez A, TripathyD,Yin X, Desobry K, Martinez J, Riley J, Gay D, Luo J, Grammas P (2012) p38 MAPK: A mediator of hypoxia-induced cerebrovascular inflammation. J Alzheimers Dis 32, 587-597.
42. Sabit R, Thomas P, Shale DJ, Collins P, Linnane SJ (2010) The effects of hypoxia on markers of coagulation and systemic inflammation in patients with COPD. Chest 138, 47-51.
43. Kaur B, KhwajaFW, Severson EA, Matheny SL, Brat DJ,Van Meir EG ( 2005) Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis. Neuro Oncol 7, 134-153.
44. Grammas P,Tripathy D,Sanchez A,Yin X,Luo J 2011 Brain microvasculature and hypoxia-related proteins in Alzheimer's disease Int J Clin Exp Pathol 4, 616-627.
45. Grammas P,OvaseR(2001) Inflammatory factors are elevated in brain microvessels in Alzheimer's disease. Neurobiol Aging 22, 837-842.
46. Thirumangalakudi L, Samany PG, Owoso A, Wiskar B, Grammas P (2006) Angiogenic proteins are expressed by brain blood vessels in Alzheimer's disease. J Alzheimers Dis 10, 111-118.
47. Chen B, Friedman B, WhitneyMA,Winkle JA, Lei IF, Olson ES, Cheng Q, Pereira B, Zhao L, Tsien RY, Lyden PD (2012) Thrombin activity associated with neuronal damage duri ng acute focal ischemia. J Neurosci 32, 7622-7631.
48. Xi G, Reiser G, Keep RF (2003) The role of thrombin and thrombin receptors in ischemic, hemorrhagic and traumatic brain injury: Deleterious or protective? J Neurochem 84, 3-9.
49. Chen B, Cheng Q,Yang K, Lyden PD (2010) Thrombin mediates severe neurovascular injury during ischemia. Stroke 41, 2348-2352.
50. Sokolova E, Reiser G (2008) Prothrombin/thrombin and the thrombin receptors PAR-1 and PAR-4 in the brain: Localization, expression and participation in neurodegenerative diseases. Thromb Haemost 100, 576-581.
51. Mhatre M, Nguyen A, Kashani S, Pham T, Adesina A, Grammas P (2004) Thrombin, a mediator of neurotoxicity and memory impairment. Neurobiol Aging 25, 783-793.
52. Mhatre M, HensleyK, Nguyen A, Grammas P (2006) Chronic thrombin exposure results in an increase in apolipoprotein-E levels. J Neurosci Res 84, 444-449.
53. Turgeon VL, Milligan CE, Houenou LJ (1999) Activation of the protease-Activated thrombin receptor (PAR)-1 ind uces motoneuron degeneration in the developing avian embryo. J Neuropathol Exp Neurol 58, 499-504.
54. Reimann-Philipp U, Ovase R,Weigel PH, Grammas P (2001) Mechanisms of cell death in primary cortical neurons and PC12 cells. J Neurosci Res 64, 657-660.
55. Park KW, Jin BK (2008) Thrombin-induced oxidative stress contributes to the death of hippocampal neurons: Role of neuronal NADPH oxidase. J Neurosci Res 86, 1053-1063.
56. Rao HV, Thirumangalakudi L, Grammas P (2009) Cyclin C and cyclin dependent kinases 1, 2 and 3 in thrombin-induced neuronal cell cycle progression and apoptosis. N eurosci Lett 450, 347-350.
57. Thirumangalakudi L, Rao HV, Grammas P (2009) Involvement of PGE2 andPGDHbut notCOX-2 in thrombin-induced cortical neuron apoptosis. Neurosci Lett 452, 172-175.
58. Festoff BW, D'Andrea MR, Citron BA, Salcedo RM, Smirnova IV, Andrade-Gordon P (2000) Motor neuron cell death in wobbler mutant mice follows overexpression of the G-protein-coupled, protease-Acti vated receptor for thrombin. Mol Med 6, 410-429.
59. Suo Z, Wu M, Citron BA, Palazzo RE, Festoff BW (2003) Rapid tau aggregation and delayed hippocampal neuronal death induced by persistent thrombin signaling. J Biol Chem 278, 37681-37689.
60. Arai T, Guo JP, McGeer PL (2005) Proteolysis of nonphosphorylated and phosphorylated tau by thrombin. J Biol Chem 280, 5145-5153.
61. Mirante O, Price M, Puentes W, Castillo X, Benakis C, Thevenet J, Monard D, Hirt L (2013) Endogenous protease nexin-1 protects against cerebral ischemia. Int J Mol Sci 14, 167 19-16731.
62. Xi G,Keep RF, Hoff JT (1998) Erythrocytes and delayed brain edema formation following intracerebral hemorrhage in rats. J Neurosurg 89, 991-996.
63. Xi G, Keep RF, Hua Y, Xiang J, Hoff JT (1999) Attenuation of thrombin-induced brain edema by cerebral thrombin preconditioning. Stroke 30, 1247-1255.
64. Ciallella JR, Figueiredo H, Smith-Swintosky V, McGillis JP (1999) Thrombin induces surface and intracellular secretion of amyloid precursor protein from human endothelial cells. Thromb Haemost 81, 630-637.
65. Igarashi K,Murai H,Asaka J 1992 Proteolytic processing of amyloid beta protein precursor (APP) by thrombin Biochem Biophys Res Commun 185, 1000-1004.
66. Akiyama H, Ikeda K, Kondo H, McGeer PL (1992) Thrombin accumulation in brains of patients with Alzheimer's disease. Neurosci Lett 146, 152-154.
67. Chodobski A, Zink BJ, Szmydynger-Chodobska J (2011) Blood-brain barrier pathophysiology in traumatic brain injury. Transl Stroke Res 2, 492-516.
68. Mortimer JA, van Duijn CM, ChandraV, Fratiglioni L, Graves AB, Heyman A, Jorm AF, Kokmen E, Kondo K, Rocca WA, et al. (1991) Head trauma as a risk factor for Alzheimer's disease: A collaborative re-Analysis of case-control studies. EURODEM Risk Factors Research Group. Int J Epidemiol 20(Suppl 2), S28-S35.
69. Ne metz PN, Leibson C, Naessens JM, Beard M, Kokmen E, Annegers JF, Kurland LT (1999) Traumatic brain injury and time to onset of Alzheimer's disease: A population-based study. Am J Epidemiol 149, 32-40.
70. Wagner SL, Geddes JW, Cotman CW, Lau AL, Gurwitz D, Isackson PJ, Cunningham DD (1989) Protease nexin-1, an antithrombin with neurite outgrowth activity, is reduced in Alzheimer disease. Proc Natl Acad Sci U S A 86, 8284-8288.
71. Vaughan PJ, Su J, Cotman CW, Cunningham DD (1994) Protease nexin-1, a potent thrombin inhibitor, is reduced around cerebral blood vessels in Alzheimer's disease. Brain Res 668, 160-170.
72. Grammas P, Martinez J, Sanchez A, Yin X, Riley J, Gay D, Desobry K, Tripathy D, Luo J, Evola M, Young A (2014) A new paradigm for the treatment of Alzheimer's disease: Targeting vascular activation. J Alzheimers Dis 40, 619-630.
73. Sanchez A, Tripathy D, Luo J, Yin X,Martinez J, Grammas P (2013) Neurovascular unit and the effects of dosage in VEGF toxicity: Role of oxidative stress and thrombin. J Alzh eimers Dis 34, 281-291.
74. Choi SH, Joe EH, Kim SU, Jin BK (2003) Thrombininduced microglial activation produces degeneration of nigral dopaminergic neurons in vivo. J Neurosci 23, 5877-5886.
75. Lin CC, Lee IT,WuWB, Liu CJ, Hsieh HL, Hsiao LD, Yang CC, Yang CM (2013) Thrombin mediates migration of rat brain astrocytes via PLC, Ca(2)(+), CaMKII, PKCalpha, and AP-1-dependent ma trix metalloproteinase-9 expression. Mol Neurobiol 48, 616-630.
76. Ji KA, Yang MS, Jou I, Shong MH, Joe EH (2004) Thrombin induces expression of cytokine-induced SH2 protein (CIS) in rat brain astrocytes: Involvement of phospholipase A2, cyclooxygenase, and lipoxygenase. Glia 48, 102-111.
77. Coughlin SR (2000) Thrombin signalling and proteaseactivated receptors. Nature 407, 258-264.
78. Colotta F, Sciacca FL, Sironi M, LuiniW , Rabiet MJ,Mantovani A (1994) Expression of monocyte chemotactic protein-1 by monocytes and endothelial cells exposed to thrombin. Am J Pathol 144, 975-985.
79. Marin V, Montero-Julian FA, Gres S, Boulay V, Bongrand P, Farnarier C, KaplanskiG(2001) The IL-6-soluble IL-6Ralpha autocrine loop of endothelial activation as an intermediate between acute and chronic inflammation: An experimental model involving thrombin. J Immun ol 167, 3435-3442.
80. Miho N, Ishida T, Kuwaba N, Ishida M, Shimote-Abe K, Tabuchi K, Oshima T, Yoshizumi M, Chayama K (2005) Role of the JNK pathway in thrombin-induced ICAM-1 ex pression in endothelial cells. Cardiovasc Res 68, 289-298.
81. Okada M, Suzuki K, Takada K, Nakashima M, Nakanishi T, Shinohara T (2006) Detection of up-regulated genes in thrombin-stimu lated human umbilical vein endothelial cells. Thromb Res 118, 715-721.
82. Grammas P, Ovase R (2002) Cerebrovascular transforming growth factor-beta contributes to inflammation in the Alzheimer's disease brain. Am J Pathol 160, 1583-1587.
83. Li DQ, Zhou YP, Yang H (2012) Donepezil combined with natural hirudin improves the clinical symptoms of patients with mild-to-moderate Alzheimer's disease:A20-we ek openlabel pilot study. Int J Med Sci 9, 248-255.
84. Garnock-Jones KP (2011) Dabigatran etexilate: A review of its use in the prevention of stroke and systemic embolism in patients with atrial fibrillation. Am J Cardiovasc Drugs 11, 57-72.
85. Bassand JP (2012) Review of atrial fibrillation outcome trials of oral anticoagulant and antiplatelet agents. Europace 14, 312-324.
86. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E,Varrone J,Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Jo yner CD,Wallentin L (2009) Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361, 1139-1151.
87. Bredesen DE, John V (2013) Next generation therapeutics for Alzheimer's disease. EMBO Mol Med 5, 795-798.
88. RamiBK(2012) Direct thrombin inhibitors potential efficacy in Alzheimer's disease.AmJ Alzheimers Dis Other Demen 27, 564-567.