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Current Alzheimer Research

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

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Research Article

Neutrophil Granule Proteins Inhibit Amyloid Beta Aggregation and Neurotoxicity

Author(s): Anne Kasus-Jacobi*, Jennifer L. Washburn, Craig A. Land and Heloise Anne Pereira

Volume 18, Issue 5, 2021

Published on: 23 August, 2021

Page: [414 - 427] Pages: 14

DOI: 10.2174/1567205018666210823095044

Price: $65

Abstract

Background: A role for neutrophils in the pathogenesis of Alzheimer’s disease (AD) is emerging. We previously showed that the neutrophil granule proteins cationic antimicrobial protein of 37 kDa (CAP37), cathepsin G (CG), and neutrophil elastase (NE) directly bind the amyloid-beta peptide Aβ1-42, a central player in AD pathogenesis. CAP37, CG, and NE are serine proteases that can cleave Aβ1-42 at different sites and with different catalytic activities.

Objective: In this study, we compared the effects of these three proteins on Aβ1-42 fibrillation and neurotoxicity.

Methods: Using mass spectrometry and in vitro aggregation assay, we found that NE and CG efficiently cleave Aβ1-42. This cleavage correlates well with the inhibition of Aβ1-42 aggregation into fibrils. In contrast, CAP37 did not efficiently cleave Aβ1-42, but was still able to inhibit its fibrillation, most likely through a quenching effect. Inhibition of Aβ1-42 aggregation by NE and CG neutralized its toxicity measured in cultured neurons. In contrast, inhibition of Aβ1-42 aggregation by CAP37 did not inhibit its neurotoxicity.

Results: We found that a peptide derived from CAP37 could mimic the quenching and inhibition of Aβ1-42 aggregation effects of the full-length protein. Additionally, this peptide was able to inhibit the neurotoxicity of the most toxic Aβ1-42 aggregate, an effect that was not found with the full-length CAP37.

Conclusion: These results shed light on the mechanisms of action of neutrophil granule proteins with regard to inhibition of Aβ1-42 aggregation and neurotoxicity and open up a possible strategy for the discovery of new disease-modifying drugs for AD.

Keywords: Alzheimer's disease, amyloid beta, neutrophil, amyloid beta degrading enzyme, bioactive peptide, neurotoxicity.

« Previous Next »
[1]
Greenhalgh AD, David S, Bennett FC. Immune cell regulation of glia during CNS injury and disease. Nat Rev Neurosci 2020; 21(3): 139-52.
[http://dx.doi.org/10.1038/s41583-020-0263-9] [PMID: 32042145]
[2]
Stock AJ, Kasus-Jacobi A, Pereira HA. The role of neutrophil granule proteins in neuroinflammation and Alzheimer’s disease. J Neuroinflammation 2018; 15(1): 240.
[http://dx.doi.org/10.1186/s12974-018-1284-4] [PMID: 30149799]
[3]
Ginhoux F, Prinz M. Origin of microglia: Current concepts and past controversies. Cold Spring Harb Perspect Biol 2015; 7(8)a020537
[http://dx.doi.org/10.1101/cshperspect.a020537] [PMID: 26134003]
[4]
Sarlus H, Heneka MT. Microglia in Alzheimer’s disease. J Clin Invest 2017; 127(9): 3240-9.
[http://dx.doi.org/10.1172/JCI90606] [PMID: 28862638]
[5]
Rossi B, Constantin G, Zenaro E. The emerging role of neutrophils in neurodegeneration. Immunobiology 2020; 225(1)151865
[http://dx.doi.org/10.1016/j.imbio.2019.10.014] [PMID: 31740077]
[6]
Heneka MT, Golenbock DT, Latz E. Innate immunity in Alzheimer’s disease. Nat Immunol 2015; 16(3): 229-36.
[http://dx.doi.org/10.1038/ni.3102] [PMID: 25689443]
[7]
Dá Mesquita S, Ferreira AC, Sousa JC, Correia-Neves M, Sousa N, Marques F. Insights on the pathophysiology of Alzheimer’s disease: The crosstalk between amyloid pathology, neuroinflammation and the peripheral immune system. Neurosci Biobehav Rev 2016; 68: 547-62.
[http://dx.doi.org/10.1016/j.neubiorev.2016.06.014] [PMID: 27328788]
[8]
Clayton KA, Van Enoo AA, Ikezu T. Alzheimer’s disease: The role of microglia in brain homeostasis and proteopathy. Front Neurosci 2017; 11: 680.
[http://dx.doi.org/10.3389/fnins.2017.00680] [PMID: 29311768]
[9]
Doens D, Fernández PL. Microglia receptors and their implications in the response to amyloid β for Alzheimer’s disease pathogenesis. J Neuroinflammation 2014; 11: 48.
[http://dx.doi.org/10.1186/1742-2094-11-48] [PMID: 24625061]
[10]
Babcock AA, Ilkjær L, Clausen BH, et al. Cytokine-producing microglia have an altered beta-amyloid load in aged APP/PS1 Tg mice. Brain Behav Immun 2015; 48: 86-101.
[http://dx.doi.org/10.1016/j.bbi.2015.03.006] [PMID: 25774009]
[11]
Koenigsknecht J, Landreth G. Microglial phagocytosis of fibrillar beta-amyloid through a beta1 integrin-dependent mechanism. J Neurosci 2004; 24(44): 9838-46.
[http://dx.doi.org/10.1523/JNEUROSCI.2557-04.2004] [PMID: 15525768]
[12]
Venegas C, Heneka MT. Danger-associated molecular patterns in Alzheimer’s disease. J Leukoc Biol 2017; 101(1): 87-98.
[http://dx.doi.org/10.1189/jlb.3MR0416-204R] [PMID: 28049142]
[13]
Zenaro E, Pietronigro E, Della Bianca V, et al. Neutrophils promote Alzheimer’s disease-like pathology and cognitive decline via LFA-1 integrin. Nat Med 2015; 21(8): 880-6.
[http://dx.doi.org/10.1038/nm.3913] [PMID: 26214837]
[14]
Baik SH, Cha MY, Hyun YM, et al. Migration of neutrophils targeting amyloid plaques in Alzheimer’s disease mouse model. Neurobiol Aging 2014; 35(6): 1286-92.
[http://dx.doi.org/10.1016/j.neurobiolaging.2014.01.003] [PMID: 24485508]
[15]
Kuyumcu ME, Yesil Y, Oztürk ZA, et al. The evaluation of neutrophil-lymphocyte ratio in Alzheimer’s disease. Dement Geriatr Cogn Disord 2012; 34(2): 69-74.
[http://dx.doi.org/10.1159/000341583] [PMID: 22922667]
[16]
Scali C, Prosperi C, Bracco L, et al. Neutrophils CD11b and fibroblasts PGE(2) are elevated in Alzheimer’s disease. Neurobiol Aging 2002; 23(4): 523-30.
[http://dx.doi.org/10.1016/S0197-4580(01)00346-3] [PMID: 12009501]
[17]
Vitte J, Michel BF, Bongrand P, Gastaut JL. Oxidative stress level in circulating neutrophils is linked to neurodegenerative diseases. J Clin Immunol 2004; 24(6): 683-92.
[http://dx.doi.org/10.1007/s10875-004-6243-4] [PMID: 15622453]
[18]
Fiala M, Lin J, Ringman J, et al. Ineffective phagocytosis of amyloid-beta by macrophages of Alzheimer’s disease patients. J Alzheimers Dis 2005; 7(3): 221-32.
[http://dx.doi.org/10.3233/JAD-2005-7304] [PMID: 16006665]
[19]
Shad KF, Aghazadeh Y, Ahmad S, Kress B. Peripheral markers of Alzheimer’s disease: Surveillance of white blood cells. Synapse 2013; 67(8): 541-3.
[http://dx.doi.org/10.1002/syn.21651] [PMID: 23404438]
[20]
Le Page A, Lamoureux J, Bourgade K, et al. Polymorphonuclear neutrophil functions are differentially altered in amnestic mild cognitive impairment and mild Alzheimer’s disease patients. J Alzheimers Dis 2017; 60(1): 23-42.
[http://dx.doi.org/10.3233/JAD-170124] [PMID: 28777750]
[21]
Dong Y, Lagarde J, Xicota L, et al. Neutrophil hyperactivation correlates with Alzheimer’s disease progression. Ann Neurol 2018; 83(2): 387-405.
[http://dx.doi.org/10.1002/ana.25159] [PMID: 29369398]
[22]
Stock AJ, Kasus-Jacobi A, Wren JD, Sjoelund VH, Prestwich GD, Pereira HA. The role of neutrophil proteins on the amyloid beta-RAGE axis. PLoS One 2016; 11(9)e0163330
[http://dx.doi.org/10.1371/journal.pone.0163330] [PMID: 27676391]
[23]
Brock AJ, Kasus-Jacobi A, Lerner M, Logan S, Adesina AM, Anne Pereira H. The antimicrobial protein, CAP37, is upregulated in pyramidal neurons during Alzheimer’s disease. Histochem Cell Biol 2015; 144(4): 293-308.
[http://dx.doi.org/10.1007/s00418-015-1347-x] [PMID: 26170148]
[24]
Nakajima K, Shimojo M, Hamanoue M, Ishiura S, Sugita H, Kohsaka S. Identification of elastase as a secretory protease from cultured rat microglia. J Neurochem 1992; 58(4): 1401-8.
[http://dx.doi.org/10.1111/j.1471-4159.1992.tb11356.x] [PMID: 1548474]
[25]
Burster T, Beck A, Poeschel S, et al. Interferon-gamma regulates cathepsin G activity in microglia-derived lysosomes and controls the proteolytic processing of myelin basic protein in vitro. Immunology 2007; 121(1): 82-93.
[http://dx.doi.org/10.1111/j.1365-2567.2007.02540.x] [PMID: 17302735]
[26]
Deane R, Du Yan S, Submamaryan RK, et al. RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med 2003; 9(7): 907-13.
[http://dx.doi.org/10.1038/nm890] [PMID: 12808450]
[27]
Cai Z, Liu N, Wang C, et al. Role of RAGE in Alzheimer’s Disease. Cell Mol Neurobiol 2016; 36(4): 483-95.
[http://dx.doi.org/10.1007/s10571-015-0233-3] [PMID: 26175217]
[28]
Chuah YK, Basir R, Talib H, Tie TH, Nordin N. Receptor for advanced glycation end products and its involvement in inflammatory diseases. Int J Inflamm 2013; 2013403460
[http://dx.doi.org/10.1155/2013/403460] [PMID: 24102034]
[29]
Yan SD, Chen X, Fu J, et al. RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. Nature 1996; 382(6593): 685-91.
[http://dx.doi.org/10.1038/382685a0] [PMID: 8751438]
[30]
Cline EN, Bicca MA, Viola KL, Klein WL. The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade. J Alzheimers Dis 2018; 64(s1): S567-610.
[http://dx.doi.org/10.3233/JAD-179941] [PMID: 29843241]
[31]
Ke PC, Sani MA, Ding F, et al. Implications of peptide assemblies in amyloid diseases. Chem Soc Rev 2017; 46(21): 6492-531.
[http://dx.doi.org/10.1039/C7CS00372B] [PMID: 28702523]
[32]
Xu MM, Ren WM, Tang XC, Hu YH, Zhang HY. Advances in development of fluorescent probes for detecting amyloid-β aggregates. Acta Pharmacol Sin 2016; 37(6): 719-30.
[http://dx.doi.org/10.1038/aps.2015.155] [PMID: 26997567]
[33]
Stine WB, Jungbauer L, Yu C, LaDu MJ. Preparing synthetic Aβ in different aggregation states. Methods Mol Biol 2011; 670: 13-32.
[http://dx.doi.org/10.1007/978-1-60761-744-0_2] [PMID: 20967580]
[34]
Kasus-Jacobi A, Noor-Mohammadi S, Griffith GL, Hinsley H, Mathias L, Pereira HA. A multifunctional peptide based on the neutrophil immune defense molecule, CAP37, has antibacterial and wound-healing properties. J Leukoc Biol 2015; 97(2): 341-50.
[http://dx.doi.org/10.1189/jlb.3A0214-104RR] [PMID: 25412625]
[35]
Griffith GL, Kasus-Jacobi A, Pereira HA. Bioactive antimicrobial peptides as therapeutics for corneal wounds and infections. Adv Wound Care (New Rochelle) 2017; 6(6): 175-90.
[http://dx.doi.org/10.1089/wound.2016.0713] [PMID: 28616359]
[36]
Sikanyika NL, Parkington HC, Smith AI, Kuruppu S. Powering amyloid beta degrading enzymes: A possible therapy for Alzheimer’s disease. Neurochem Res 2019; 44(6): 1289-96.
[http://dx.doi.org/10.1007/s11064-019-02756-x] [PMID: 30806879]
[37]
Murphy MP, LeVine H III. Alzheimer’s disease and the amyloid-beta peptide. J Alzheimers Dis 2010; 19(1): 311-23.
[http://dx.doi.org/10.3233/JAD-2010-1221] [PMID: 20061647]
[38]
Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 2016; 8(6): 595-608.
[http://dx.doi.org/10.15252/emmm.201606210] [PMID: 27025652]
[39]
Kuruppu S, Rajapakse NW, Spicer AJ, Parkington HC, Smith AI. Stimulating the activity of amyloid-beta degrading enzymes: A novel approach for the therapeutic manipulation of amyloid-beta levels. J Alzheimers Dis 2016; 54(3): 891-5.
[http://dx.doi.org/10.3233/JAD-160492] [PMID: 27567865]
[40]
Kosikowska P, Lesner A. Inhibitors of cathepsin G: A patent review (2005 to present). Expert Opin Ther Pat 2013; 23(12): 1611-24.
[41]
Crocetti L, Quinn MT, Schepetkin IA, Giovannoni MP. A patenting perspective on human neutrophil elastase (HNE) inhibitors (2014-2018) and their therapeutic applications. Expert Opin Ther Pat 2019; 29(7): 555-78.
[42]
Korkmaz B, Moreau T, Gauthier F. Neutrophil elastase, proteinase 3 and cathepsin G: Physicochemical properties, activity and physiopathological functions. Biochimie 2008; 90(2): 227-42.
[http://dx.doi.org/10.1016/j.biochi.2007.10.009] [PMID: 18021746]
[43]
Pereira HA, Spitznagel JK, Pohl J, et al. CAP 37, a 37 kD human neutrophil granule cationic protein shares homology with inflammatory proteinases. Life Sci 1990; 46(3): 189-96.
[http://dx.doi.org/10.1016/0024-3205(90)90104-Y] [PMID: 2406527]
[44]
Campanelli D, Detmers PA, Nathan CF, Gabay JE. Azurocidin and a homologous serine protease from neutrophils. Differential antimicrobial and proteolytic properties. J Clin Invest 1990; 85(3): 904-15.
[http://dx.doi.org/10.1172/JCI114518] [PMID: 2312733]
[45]
Karlsen S, Iversen LF, Larsen IK, Flodgaard HJ, Kastrup JS. Atomic resolution structure of human HBP/CAP37/azurocidin. Acta Crystallogr D Biol Crystallogr 1998; 54(Pt 4): 598-609.
[http://dx.doi.org/10.1107/S0907444997016193] [PMID: 9761855]

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