Generic placeholder image

Current Alzheimer Research

Editor-in-Chief

ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Research Article

Glial-derived Neuroinflammation induced with Amyloid-beta-peptide Plus Fibrinogen Injection in Rat Hippocampus

Author(s): James G. McLarnon*

Volume 20, Issue 7, 2023

Published on: 28 September, 2023

Page: [515 - 522] Pages: 8

DOI: 10.2174/1567205020666230912113501

Price: $65

Abstract

Introduction: The present study has examined microglial and astrocyte activation in association with neuronal degeneration in an animal model using an injection of amyloid-beta peptide Aβ1-42 (Aβ42) plus fibrinogen into rat hippocampus.

Methods: The combination of stimuli is suggested as a novel and potent perturbation to induce gliosis and the production of glial-derived neurotoxic factors in an animal model exhibiting a leaky BBB (blood-brain barrier). Specifically, Aβ42 + fibrinogen stimulation elevated levels of COX-2 (cyclooxygenase-2) and iNOS (inducible nitric oxide synthase) with a considerable extent of neuronal loss associated with microglia and astrocyte activation.

Results: Treatment of injected rats with the broad spectrum anti-inflammatory agent, minocycline or the iNOS inhibitor, 1400 W inhibited gliosis, reduced levels of COX-2 and iNOS, and demonstrated efficacy for neuroprotection.

Conclusion: The findings suggest the utility of combining amyloid beta peptide plus fibrinogen as a potent and understudied neuroinflammatory stimulus for the induction of glial-derived neurotoxic factors in BBB-compromised AD brain.

« Previous
[1]
Zlokovic, B.V. Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat. Rev. Neurosci., 2011, 12(12), 723-738.
[http://dx.doi.org/10.1038/nrn3114] [PMID: 22048062]
[2]
Montagne, A.; Zhao, Z.; Zlokovic, B.V. Alzheimer’s disease: A matter of blood–brain barrier dysfunction? J. Exp. Med., 2017, 214(11), 3151-3169.
[http://dx.doi.org/10.1084/jem.20171406] [PMID: 29061693]
[3]
Sweeney, M.D.; Sagare, A.P.; Zlokovic, B.V. Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat. Rev. Neurol., 2018, 14(3), 133-150.
[http://dx.doi.org/10.1038/nrneurol.2017.188] [PMID: 29377008]
[4]
Montagne, A.; Barnes, S.R.; Sweeney, M.D.; Halliday, M.R.; Sagare, A.P.; Zhao, Z.; Toga, A.W.; Jacobs, R.E.; Liu, C.Y.; Amezcua, L.; Harrington, M.G.; Chui, H.C.; Law, M.; Zlokovic, B.V. Blood-brain barrier breakdown in the aging human hippocampus. Neuron, 2015, 85(2), 296-302.
[http://dx.doi.org/10.1016/j.neuron.2014.12.032] [PMID: 25611508]
[5]
Nation, D.A.; Sweeney, M.D.; Montagne, A.; Sagare, A.P.; D’Orazio, L.M.; Pachicano, M.; Sepehrband, F.; Nelson, A.R.; Buennagel, D.P.; Harrington, M.G.; Benzinger, T.L.S.; Fagan, A.M.; Ringman, J.M.; Schneider, L.S.; Morris, J.C.; Chui, H.C.; Law, M.; Toga, A.W.; Zlokovic, B.V. Blood–brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat. Med., 2019, 25(2), 270-276.
[http://dx.doi.org/10.1038/s41591-018-0297-y] [PMID: 30643288]
[6]
Paul, J.; Strickland, S.; Melchor, J.P. Fibrin deposition accelerates neurovascular damage and neuroinflammation in mouse models of Alzheimer’s disease. J. Exp. Med., 2007, 204(8), 1999-2008.
[http://dx.doi.org/10.1084/jem.20070304] [PMID: 17664291]
[7]
Cortes-Canteli, M.; Paul, J.; Norris, E.H.; Bronstein, R.; Ahn, H.J.; Zamolodchikov, D.; Bhuvanendran, S.; Fenz, K.M.; Strickland, S. Fibrinogen and beta-amyloid association alters thrombosis and fibrinolysis: A possible contributing factor to Alzheimer’s disease. Neuron, 2010, 66(5), 695-709.
[http://dx.doi.org/10.1016/j.neuron.2010.05.014] [PMID: 20547128]
[8]
Ryu, J.K.; McLarnon, J.G. A leaky blood-brain barrier, fibrinogen infiltration and microglial reactivity in inflamed Alzheimer’s disease brain. J. Cell. Mol. Med., 2009, 13(9a), 2911-2925.
[http://dx.doi.org/10.1111/j.1582-4934.2008.00434.x] [PMID: 18657226]
[9]
Cortes-Canteli, M.; Mattei, L.; Richards, A.T.; Norris, E.H.; Strickland, S. Fibrin deposited in the Alzheimer’s disease brain promotes neuronal degeneration. Neurobiol. Aging, 2015, 36(2), 608-617.
[http://dx.doi.org/10.1016/j.neurobiolaging.2014.10.030] [PMID: 25475538]
[10]
Ryu, J.K.; McLarnon, J.G. Thalidomide inhibition of perturbed vasculature and glial-derived tumor necrosis factor-α in an animal model of inflamed Alzheimer’s disease brain. Neurobiol. Dis., 2008, 29(2), 254-266.
[http://dx.doi.org/10.1016/j.nbd.2007.08.019] [PMID: 17964176]
[11]
Merlini, M.; Rafalski, V.A.; Rios Coronado, P.E.; Gill, T.M.; Ellisman, M.; Muthukumar, G.; Subramanian, K.S.; Ryu, J.K.; Syme, C.A.; Davalos, D.; Seeley, W.W.; Mucke, L.; Nelson, R.B.; Akassoglou, K. Fibrinogen induces microglia-mediated spine elimination and cognitive impairment in an Alzheimer’s disease model. Neuron, 2019, 101(6), 1099-1108.e6.
[http://dx.doi.org/10.1016/j.neuron.2019.01.014] [PMID: 30737131]
[12]
Ryu, J.K.; Franciosi, S.; Sattayaprasert, P.; Kim, S.U.; McLarnon, J.G. Minocycline inhibits neuronal death and glial activation induced by beta-amyloid peptide in rat hippocampus. Glia, 2004, 48(1), 85-90.
[http://dx.doi.org/10.1002/glia.20051] [PMID: 15326618]
[13]
Ryu, J.K.; McLarnon, J.G. Minocycline or iNOS inhibition block 3-nitrotyrosine increases and blood–brain barrier leakiness in amyloid beta-peptide-injected rat hippocampus. Exp. Neurol., 2006, 198(2), 552-557.
[http://dx.doi.org/10.1016/j.expneurol.2005.12.016] [PMID: 16480717]
[14]
Ryu, J.K.; Cho, T.; Choi, H.B.; Wang, Y.T.; McLarnon, J.G. Microglial VEGF receptor response is an integral chemotactic component in Alzheimer’s disease pathology. J. Neurosci., 2009, 29(1), 3-13.
[http://dx.doi.org/10.1523/JNEUROSCI.2888-08.2009] [PMID: 19129379]
[15]
Ryu, J.K.; Cho, T.; Choi, H.B.; Jantaratnotai, N.; McLarnon, J.G. Pharmacological antagonism of interleukin-8 receptor CXCR2 inhibits inflammatory reactivity and is neuroprotective in an animal model of Alzheimer’s disease. J. Neuroinflammation, 2015, 12(1), 144.
[http://dx.doi.org/10.1186/s12974-015-0339-z] [PMID: 26255110]
[16]
Strickland, S. Blood will out: Vascular contributions to Alzheimer’s disease. J. Clin. Invest., 2018, 128(2), 556-563.
[http://dx.doi.org/10.1172/JCI97509] [PMID: 29388925]
[17]
Petersen, M.A.; Ryu, J.K.; Akassoglou, K. Fibrinogen in neurological diseases: Mechanisms, imaging and therapeutics. Nat. Rev. Neurosci., 2018, 19(5), 283-301.
[http://dx.doi.org/10.1038/nrn.2018.13] [PMID: 29618808]
[18]
Norris, E.H.; Strickland, S. Fibrinogen in the nervous system: Glia beware. Neuron, 2017, 96(5), 951-953.
[http://dx.doi.org/10.1016/j.neuron.2017.11.021] [PMID: 29216454]
[19]
Guan, P.P.; Wang, P. Integrated communications between cyclooxygenase-2 and Alzheimer’s disease. FASEB J., 2019, 33(1), 13-33.
[http://dx.doi.org/10.1096/fj.201800355RRRR] [PMID: 30020833]
[20]
Lee, S.C.; Zhao, M.L.; Hirano, A.; Dickson, D.W. Inducible nitric oxide synthase immunoreactivity in the Alzheimer disease hippocampus: Association with Hirano bodies, neurofibrillary tangles, and senile plaques. J. Neuropathol. Exp. Neurol., 1999, 58(11), 1163-1169.
[http://dx.doi.org/10.1097/00005072-199911000-00006] [PMID: 10560659]
[21]
Ryu, J.K.; Davalos, D.; Akassoglou, K. Fibrinogen signal transduction in the nervous system. J. Thromb. Haemost., 2009, 7(Suppl 1), 151-154.
[http://dx.doi.org/10.1111/j.1538-7836.2009.03438.x] [PMID: 19630789]
[22]
Simpson, D.S.A.; Oliver, P.L. ROS generation in microglia: Understanding oxidative stress and inflammation in neurodegenerative disease. Antioxidants, 2020, 9(8), 743.
[http://dx.doi.org/10.3390/antiox9080743] [PMID: 32823544]
[23]
McLarnon, J.G. A leaky blood-brain barrier to fibrinogen contributes to oxidative damage in Alzheimer’s disease. Antioxidants, 2022, 11(1), 102.
[http://dx.doi.org/10.3390/antiox11010102] [PMID: 35052606]
[24]
Ahn, H.J.; Zamolodchikov, D.; Cortes-Canteli, M.; Norris, E.H.; Glickman, J.F.; Strickland, S. Alzheimer’s disease peptide β-amyloid interacts with fibrinogen and induces its oligomerization. Proc. Natl. Acad. Sci., 2010, 107(50), 21812-21817.
[http://dx.doi.org/10.1073/pnas.1010373107] [PMID: 21098282]
[25]
Zamolodchikov, D.; Strickland, S. Aβ delays fibrin clot lysis by altering fibrin structure and attenuating plasminogen binding to fibrin. Blood, 2012, 119(14), 3342-3351.
[http://dx.doi.org/10.1182/blood-2011-11-389668] [PMID: 22238323]
[26]
Liddelow, S.A.; Guttenplan, K.A.; Clarke, L.E.; Bennett, F.C.; Bohlen, C.J.; Schirmer, L.; Bennett, M.L.; Münch, A.E.; Chung, W.S.; Peterson, T.C.; Wilton, D.K.; Frouin, A.; Napier, B.A.; Panicker, N.; Kumar, M.; Buckwalter, M.S.; Rowitch, D.H.; Dawson, V.L.; Dawson, T.M.; Stevens, B.; Barres, B.A. Neurotoxic reactive astrocytes are induced by activated microglia. Nature, 2017, 541(7638), 481-487.
[http://dx.doi.org/10.1038/nature21029] [PMID: 28099414]
[27]
Park, JS; Kam, TI; Lee, S; Park, H; Oh, Y Blocking microglial activation of reactive astrocytes is neuroprotective in models of Alzheimer’s disease. Acta Neuropath Comm, 2021, 9(1), 78.
[http://dx.doi.org/10.1186/s40478-021-01180-z]
[28]
Klegeris, A.; Hashioka, S.; McLarnon, J.G. Diversity and regulation of astrocyte neurotoxicity in Alzheimer’s disease. Curr. Alzheimer Res., 2021, 18(12), 925-938.
[http://dx.doi.org/10.2174/1567205018666211117100342] [PMID: 34789126]
[29]
Grammas, P. Neurovascular dysfunction, inflammation and endothelial activation: Implications for the pathogenesis of Alzheimer’s disease. J. Neuroinflammation, 2011, 8(1), 26.
[http://dx.doi.org/10.1186/1742-2094-8-26] [PMID: 21439035]
[30]
Ransohoff, R.M. All (animal) models (of neurodegeneration) are wrong. Are they also useful? J. Exp. Med., 2018, 215(12), 2955-2958.
[http://dx.doi.org/10.1084/jem.20182042] [PMID: 30459159]
[31]
Jantaratnotai, N.; Ryu, J.K.; Schwab, C.; McGeer, P.L.; McLarnon, J.G. Comparison of vascular perturbations in an Aβ-injected animal model and in AD brain. Int J Alz Dis, 2011, 2011, 918280.
[http://dx.doi.org/10.4061/2011/918280]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy