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Anti-amyloidogenic, anti-oxidant and anti-apoptotic role of gelsolin in Alzheimer’s disease

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Abstract

Fibrillar amyloid beta-protein (Aβ) is a major component of amyloid plaques in the brains of individuals with Alzheimer’s disease (AD) and of adults with Down syndrome (DS). Gelsolin, a cytoskeletal protein, is present both intracellularly (cytoplasmic form) and extracellularly (secretory form in biological fluids). These two forms of gelsolin differ from each other in length and in cysteinyl thiol groups. Previous studies from our and other groups have identified the anti-amyloidogenic role of gelsolin in AD. Our studies showed that both plasma and cytosolic gelsolin bind to Aβ, and that gelsolin inhibits the fibrillization of Aβ and solubilizes preformed fibrils of Aβ. Other studies have shown that peripheral administration of plasma gelsolin or transgene expression of plasma gelsolin can reduce amyloid load in the transgenic mouse model of AD. Our recent studies showed that gelsolin expression increases in cells in response to oxidative stress. Oxidative damage is considered a major feature in the pathophysiology of AD. Aβ not only can induce oxidative stress, but also its generation is increased as a result of oxidative stress. In this article, we review evidence of gelsolin as an anti-amyloidogenic agent that can reduce amyloid load by acting as an inhibitor of Aβ fibrillization, and as an antioxidant and anti-apoptotic protein.

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References

  • Ali FE, Separovic F, Barrow CJ et al (2005) Methionine regulates copper/hydrogen peroxide oxidation products of Abeta. J Pept Sci 11:353–360. doi:10.1002/psc.626

    Article  PubMed  CAS  Google Scholar 

  • Arlt S, Beisiegel U, Kontush A (2002) Lipid peroxidation in neurodegeneration: new insights into Alzheimer’s disease. Curr Opin Lipidol 13:289–294. doi:10.1097/00041433-200206000-00009

    Article  PubMed  CAS  Google Scholar 

  • Bandopadhyay U, Dipak D, Banerjee RK (1999) Reactive oxygen species: oxidative damage and pathogenesis. Curr Sci 77:658–666

    Google Scholar 

  • Behl C (2005) Oxidative stress in Alzheimer’s disease: implications for prevention and therapy. Subcell Biochem 38:65–78. doi:10.1007/0-387-23226-5_3

    Article  PubMed  CAS  Google Scholar 

  • Chauhan V, Chauhan A (2006) Oxidative stress in Alzheimer’s disease. Pathophysiol 13:195–208. doi:10.1016/j.pathophys.2006.05.004

    Article  CAS  Google Scholar 

  • Chauhan A, Chauhan VPS, Wegiel J et al (1996a) Impact of normal and heat-inactivated serum on in-vitro aggregation and fibrillization of synthetic amyloid beta-protein. Alzheimer’s Res 2:243–248

    CAS  Google Scholar 

  • Chauhan A, Pirttila T, Mehta P et al (1996b) Effect of cerebrospinal fluid from normal and Alzheimer’s patients with different apolipoprotein E phenotypes on in vitro aggregation of amyloid beta-protein. J Neurol Sci 141:54–58. doi:10.1016/0022-510X(96)00123-2

    Article  PubMed  CAS  Google Scholar 

  • Chauhan A, Chauhan VPS, Rubenstein R et al (1997a) Media from rhabdomyosarcoma and neuroblastoma cell cultures stimulate in vitro aggregation and fibrillization of amyloid beta-protein. Neurochem Res 22:227–232. doi:10.1023/A:1027379926976

    Article  PubMed  CAS  Google Scholar 

  • Chauhan VPS, Ray I, Chauhan A et al (1997b) Metal cations defibrillize the amyloid beta-protein fibrils. Neurochem Res 22:805–809. doi:10.1023/A:1022079709085

    Article  PubMed  CAS  Google Scholar 

  • Chauhan VPS, Ray I, Chauhan A et al (1999) Binding of gelsolin, a secretory protein, to amyloid β-protein. Biochem Biophys Res Commun 258:241–246. doi:10.1006/bbrc.1999.0623

    Article  PubMed  CAS  Google Scholar 

  • Dikalov SI, Vitek MP, Mason RP (2004) Cupric-amyloid beta peptide complex stimulates oxidation of ascorbate and generation of hydroxyl radical. Free Radic Biol Med 36:340–347. doi:10.1016/j.freeradbiomed.2003.11.004

    Article  PubMed  CAS  Google Scholar 

  • Eun DW, Ahn SH, You JS et al (2007) PKC epsilon is essential for gelsolin expression by histone deacetylase inhibitor apicidin in human cervix cancer cells. Biochem Biophys Res Commun 354:769–775. doi:10.1016/j.bbrc.2007.01.046

    Article  PubMed  CAS  Google Scholar 

  • Forloni G (1996) Neurotoxicity of beta-amyloid and prion peptides. Curr Opin Neurol 9:492–500. doi:10.1097/00019052-199612000-00017

    Article  PubMed  CAS  Google Scholar 

  • Furukawa K, Fu W, Li Y et al (1997) The actin-severing protein gelsolin modulates calcium channel and NMDA receptor activities and vulnerability to excitotoxicity in hippocampal neurons. J Neurosci 17:8178–8186

    PubMed  CAS  Google Scholar 

  • Gabbita SP, Lovell MA, Markesbery WR (1998) Increased nuclear DNA oxidation in the brain in Alzheimer’s disease. J Neurochem 71:2034–2040

    PubMed  CAS  Google Scholar 

  • Ghiso J, Matsubara E, Koudinov A et al (1993) The cerebrospinal fluid soluble form of Alzheimer’s amyloid β is complexed to SP-40, 40 (APO J), an inhibitor of the complement membrane attack complex. Biochem J 293:27–30

    PubMed  CAS  Google Scholar 

  • Glenner GG (1983) Alzheimer’s disease: the commonest form of amyloidosis. Arch Pathol Lab Med 107:281–282

    PubMed  CAS  Google Scholar 

  • Golabek AA, Soto C, Vogel T et al (1996) The interaction between apolipoprotein E and Alzheimer’s amyloid beta-peptide is dependent on beta-peptide conformation. J Biol Chem 271:10602–10606. doi:10.1074/jbc.271.52.33623

    Article  PubMed  CAS  Google Scholar 

  • Haass C, Schlossmacher MG, Hung AY et al (1992) Amyloid beta-peptide is produced by cultured cells during normal metabolism. Nature 359:322–325. doi:10.1038/359414a0

    Article  PubMed  CAS  Google Scholar 

  • Hartley DM, Walsh DM, Ye CP et al (1999) Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons. J Neurosci 19:8876–8884

    PubMed  CAS  Google Scholar 

  • Hilbich C, Kisters-Woike B, Reed J et al (1991) Aggregation and secondary structure of synthetic amyloid beta A4 peptides of Alzheimer’s disease. J Mol Biol 218:149–163. doi:10.1016/0022-2836(91)90881-6

    Article  PubMed  CAS  Google Scholar 

  • Hirko AC, Meyer EM, King MA et al (2007) Peripheral transgene expression of plasma gelsolin reduces amyloid in transgenic mouse models of Alzheimer’s disease. Mol Ther 15:1623–1629. doi:10.1038/sj.mt.6300253

    Article  PubMed  CAS  Google Scholar 

  • Iversen LL, Mortishire-Smith RJ, Pollack SJ et al (1995) The toxicity in vitro of β-amyloid protein. Biochem J 311:1–16

    PubMed  CAS  Google Scholar 

  • Jang JH, Surh YJ (2004) Possible role of NF-kappaB in Bcl-X(L) protection against hydrogen peroxide-induced PC12 cell death. Redox Rep 9:343–348. doi:10.1179/135100004225006858

    Article  PubMed  CAS  Google Scholar 

  • Janmay PA (1994) Phosphoinositides and calcium as regulators of cellular actin assembly and disassembly. Annu Rev Physiol 56:169–191

    Google Scholar 

  • Jhoo JH, Kim HC, Nabeshima T et al (2004) Beta-amyloid (1-42)-induced learning and memory deficits in mice: involvement of oxidative burdens in the hippocampus and cerebral cortex. Behav Brain Res 155:185–196. doi:10.1016/j.bbr.2004.04.012

    Article  PubMed  CAS  Google Scholar 

  • Ji L, Chauhan A, Chauhan V (2008) Cytoplasmic gelsolin in pheochromocytoma-12 cells forms a complex with amyloid beta-protein. Neuroreport 19:463–466

    Article  PubMed  CAS  Google Scholar 

  • Kang J, Lemaire HG, Unterbeck A et al (1987) The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 325:733–736. doi:10.1038/325733a0

    Article  PubMed  CAS  Google Scholar 

  • Kim HC, Yamada K, Nitta A (2003) Immunocytochemical evidence that amyloid beta (1-42) impairs endogenous antioxidant systems in vivo. Neuroscience 119:399–419. doi:10.1016/S0306-4522(02)00993-4

    Article  PubMed  CAS  Google Scholar 

  • Kirkitadze MD, Kowalska A (2005) Molecular mechanisms initiating amyloid beta-fibril formation in Alzheimer’s disease. Acta Biochim Pol 52:417–423

    PubMed  CAS  Google Scholar 

  • Kothakota S, Azuma T, Reinhard C et al (1997) Caspase-3-generated fragment of gelsolin: effector of morphological changes in apoptosis. Science 278:294–298. doi:10.1126/science.278.5336.294

    Article  PubMed  CAS  Google Scholar 

  • Koudinov A, Matsubara E, Frangione B et al (1994) The soluble form of Alzheimer’s amyloid beta-protein is complexed to high-density lipoprotein 3 and very high density lipoprotein in normal human plasma. Biochem Biophys Res Commun 205:1164–1171. doi:10.1006/bbrc.1994.2788

    Article  PubMed  CAS  Google Scholar 

  • Kuzumaki N, Tanaka M, Sakai N et al (1997) Tumor suppressive function of gelsolin. Gan To Kagaku Ryoho 24:1436–1441

    PubMed  CAS  Google Scholar 

  • Kwiatkowski DJ, Mehl R, Ying HL (1988) Genomic organization and biosynthesis of secreted and cytoplasmic forms of gelsolin. J Cell Biol 106:375–384. doi:10.1083/jcb.106.2.375

    Article  PubMed  CAS  Google Scholar 

  • Lambert MP, Barlow AK, Chromy BA et al (1998) Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci USA 95:6448–6453. doi:10.1073/pnas.95.11.6448

    Article  PubMed  CAS  Google Scholar 

  • Levy E, Carman MD, Fernandez-Madrid IJ et al (1990) Mutation of the Alzheimer’s disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science 248:1124–1126. doi:10.1126/science.2111584

    Article  PubMed  CAS  Google Scholar 

  • Lorenzo A, Yanker BA (1994) β-Amyloid neurotoxicity requires fibril formation and is inhibited by Congo red. Proc Natl Acad Sci USA 91:12243–12247. doi:10.1073/pnas.91.25.12243

    Article  PubMed  CAS  Google Scholar 

  • Lovell MA, Gabbita SP, Markesbery WR (1999) Increased DNA oxidation and decreased levels of repair products in Alzheimer’s disease ventricular CSF. J Neurochem 72:771–776. doi:10.1046/j.1471-4159.1999.0720771.x

    Article  PubMed  CAS  Google Scholar 

  • Lyras L, Cairns NJ, Jenner A et al (1997) An assessment of oxidative damage to proteins, lipids, and DNA in brain from patients with Alzheimer’s disease. J Neurochem 68:2061–2069

    PubMed  CAS  Google Scholar 

  • McDonagh B, Sheehan D (2007) Effect of oxidative stress on protein thiols in the blue mussel Mytilus edulis: proteomic identification of target proteins. Proteomics 7:3395–3403. doi:10.1002/pmic.200700241

    Article  PubMed  CAS  Google Scholar 

  • Masters CL, Simms G, Weinman NA et al (1985) Amyloid plaque core protein in Alzheimer’s disease and Down’s syndrome. Proc Natl Acad Sci USA 82:4245–4249. doi:10.1073/pnas.82.12.4245

    Article  PubMed  CAS  Google Scholar 

  • Markesbery WR, Carney JM (1999) Oxidative alterations in Alzheimer’s disease. Brain Pathol 9:133–146

    PubMed  CAS  Google Scholar 

  • Matsumoto N, Kitayama H, Kitada M et al (2003) Isolation of a set of genes expressed in the choroid plexus of the mouse using suppression subtractive hybridization. Neuroscience 117:405–415. doi:10.1016/S0306-4522(02)00827-8

    Article  PubMed  CAS  Google Scholar 

  • Matsuoka Y, Saito M, LaFrancois J et al (2003) Novel therapeutic approach for the treatment of Alzheimer’s disease by peripheral administration of agents with an affinity to beta-amyloid. J Neurosci 23:29–33

    PubMed  CAS  Google Scholar 

  • Maury CP, Sletten K, Totty N et al (1997) Identification of the circulating amyloid precursor and other gelsolin metabolites in patients with G654A mutation in the gelsolin gene (Finnish familial amyloidosis): pathogenetic and diagnostic implications. Lab Invest 77:299–304

    PubMed  CAS  Google Scholar 

  • Mazur-Kolecka B, Kowal D, Sukontasup T et al (2003) The effect of oxidative stress on accumulation of apolipoprotein E3 and E4 in a cell culture model of beta-amyloid angiopathy (CAA). Brain Res 983:48–57. doi:10.1016/S0006-8993(03)03026-9

    Article  PubMed  CAS  Google Scholar 

  • Mohmmad AH, Wenk GL, Gramling M et al (2004) APP and PS-1 mutations induce brain oxidative stress independent of dietary cholesterol: implications for Alzheimer’s disease. Neurosci Lett 368:148–150. doi:10.1016/j.neulet.2004.06.077

    Article  CAS  Google Scholar 

  • Murphy B, Kirszbaum L, Walker I et al (1988) SP-40, 40, a newly identified normal human serum protein found in SC5b-9 complex of complement and in the immune deposits in glemerulonephritis. J Clin Invest 81:1858–1864. doi:10.1172/JCI113531

    Article  PubMed  CAS  Google Scholar 

  • Park L, Anrather J, Forster C et al (2004) Abeta-induced vascular oxidative stress and attenuation of functional hyperemia in mouse somatosensory cortex. J Cereb Blood Flow Metab 24:334–342. doi:10.1097/01.WCB.0000105800.49957.1E

    Article  PubMed  CAS  Google Scholar 

  • Paunio T, Kiuru S, Karonen S et al (1994) Quantification of gelsolin in the serum of familial amyloidosis, Finnish type (Agel). Amyloid Int J Exp Clin Invest 1:80–89

    CAS  Google Scholar 

  • Pitas R, Boyles J, Lee S et al (1987) Lipoproteins and their receptors in the central nervous system, characterization of the lipoproteins in cerebrospinal fluid and identification of apolipoprotein B, E (LDL) receptors in the brain. J Biol Chem 262:14352–14360

    PubMed  CAS  Google Scholar 

  • Qiao H, Koya RC, Nakagawa K (2005) Inhibition of Alzheimer’s amyloid-beta peptide-induced reduction of mitochondrial membrane potential and neurotoxicity by gelsolin. Neurobiol Aging 26:849–855. doi:10.1016/j.neurobiolaging.2004.08.003

    Article  PubMed  CAS  Google Scholar 

  • Ray I, Chauhan A, Wegiel J et al (2000) Gelsolin inhibits the fibrillization of amyloid beta-protein, and also defibrillizes its preformed fibrils. Brain Res 853:344–351. doi:10.1016/S0006-8993(99)02315-X

    Article  PubMed  CAS  Google Scholar 

  • Sastre M, Steiner H, Fuchs K et al (2001) Presenilin-dependent gamma-secretase processing of beta-amyloid precursor protein at a site corresponding to the S3 cleavage of Notch. EMBO Rep 2:835–841. doi:10.1093/embo-reports/kve180

    Article  PubMed  CAS  Google Scholar 

  • Schuessel K, Schafer S, Bayer TA et al (2005) Impaired Cu/Zn-SOD activity contributes to increased oxidative damage in APP transgenic mice. Neurobiol Dis 18:89–99. doi:10.1016/j.nbd.2004.09.003

    Article  PubMed  CAS  Google Scholar 

  • Serpell LC, Sunde M, Benson MD et al (2000) The protofilament substructure of amyloid fibrils. J Mol Biol 300:1033–1039. doi:10.1006/jmbi.2000.3908

    Article  PubMed  CAS  Google Scholar 

  • Seubert P, Vigo-Pelfrey C, Esch F et al (1992) Isolation and quantitation of soluble Alzheimer’s beta-peptide from biological fluids. Nature 359:325–327. doi:10.1038/359325a0

    Article  PubMed  CAS  Google Scholar 

  • Stossel TP (1990) Actin-membrane interactions in eukaryotic mammalian cells. In: Hoffman JF, Giebisch G (eds) Current topics in membranes and transport, vol 36. Academic Press, NY, pp 97–107

    Google Scholar 

  • Strittmatter WJ, Weisgraber KH, Huang DY et al (1993) Binding of human apolipoprotein E to synthetic amyloid β-peptide: isoform-specific effects and implications for late-onset Alzheimer’s disease. Proc Natl Acad Sci USA 90:8098–8102. doi:10.1073/pnas.90.17.8098

    Article  PubMed  CAS  Google Scholar 

  • Sultana R, Ravagna A, Mohmmad-Abdul H et al (2005) Ferulic acid ethyl ester protects neurons against amyloid beta-peptide (1-42)-induced oxidative stress and neurotoxicity: relationship to antioxidant activity. J Neurochem 92:749–758. doi:10.1111/j.1471-4159.2004.02899.x

    Article  PubMed  CAS  Google Scholar 

  • Tamagno E, Robino G, Obbili A et al (2003) H2O2 and 4-hydroxynonenal mediate amyloid beta-induced neuronal apoptosis by activating JNKs and p38MAPK. Exp Neurol 180:144–155. doi:10.1016/S0014-4886(02)00059-6

    Article  PubMed  CAS  Google Scholar 

  • Tanaka J, Sobue K (1994) Localization and characterization of gelsolin in nervous tissues: gelsolin is specifically enriched in myelin-forming cells. J Neurosci 14:1038–1052

    PubMed  CAS  Google Scholar 

  • Vardy ER, Catto AJ, Hooper NM (2005) Proteolytic mechanisms in amyloid-beta metabolism: therapeutic implications for Alzheimer’s disease. Trends Mol Med 11:464–472. doi:10.1016/j.molmed.2005.08.004

    Article  PubMed  CAS  Google Scholar 

  • Vassar R, Bennett BD, Babu-Khan S et al (1999) Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286:735–741. doi:10.1126/science.286.5440.735

    Article  PubMed  CAS  Google Scholar 

  • Vigo-Pelfrey C, Lee D, Keim P et al (1993) Characterization of β-amyloid peptide from human cerebrospinal fluid. J Neurochem 61:1965–1968. doi:10.1111/j.1471-4159.1993.tb09841.x

    Article  PubMed  CAS  Google Scholar 

  • Vouyiouklis DA, Brophy PJ (1997) A novel gelsolin isoform expressed by oligodendrocytes in the central nervous system. J Neurochem 69:995–1005

    Article  PubMed  CAS  Google Scholar 

  • Walsh DM, Hartley DM, Kusumoto Y et al (1999) Amyloid beta-protein fibrillogenesis Structure and biological activity of protofibrillar intermediates. J Biol Chem 274:25945–25952. doi:10.1074/jbc.274.36.25945

    Article  PubMed  CAS  Google Scholar 

  • Wegiel J, Chauhan A, Wisniewski HM et al (1996) Promotion of synthetic amyloid β-peptide fibrillization by cell culture media and abolishment of fibrillization by serum. Neurosci Lett 211:151–154. doi:10.1016/0304-3940(96)12739-7

    Article  PubMed  CAS  Google Scholar 

  • Wen D, Corina K, Chow EP et al (1996) The plasma and cytoplasmic forms of human gelsolin differ in disulfide structure. Biochemistry 35:9700–9709. doi:10.1021/bi960920n

    Article  PubMed  CAS  Google Scholar 

  • Wisniewski HM, Wegiel J, Kotula L (1996) Some neuropathology aspects of Alzheimer’s disease and its relevance to other disciplines. Neuropathol Appl Neurobiol 22:3–11. doi:10.1111/j.1365-2990.1996.tb00839.x

    Article  PubMed  CAS  Google Scholar 

  • Wisniewski T, Ghiso J, Frangione B (1997) Biology of Aβ amyloid in Alzheimer’s disease. Neurobiol Dis 4:313–328. doi:10.1006/nbdi.1997.0147

    Article  PubMed  CAS  Google Scholar 

  • Wujek JR, Dority MD, Frederickson RC et al (1996) Deposits of Abeta fibrils are not toxic to cortical and hippocampal neurons in vitro. Neurobiol Aging 1:107–113. doi:10.1016/0197-4580(95)02020-9

    Article  Google Scholar 

  • Younkin SG (1995) Evidence that Aβ 42 is the real culprit in Alzheimer’s disease. Ann Neurol 37:287–288. doi:10.1002/ana.410370303

    Article  PubMed  CAS  Google Scholar 

  • Yu C, Kim SH, Ikeuchi T et al (2001) Characterization of a presenilin-mediated amyloid precursor protein carboxyl-terminal fragment gamma. Evidence for distinct mechanisms involved in gamma-secretase processing of the APP and Notch1 transmembrane domains. J Biol Chem 276:43756–43760. doi:10.1074/jbc.C100410200

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported in part by the funds from the New York State Office of Mental Retardation and Developmental Disabilities, and by NIH Grant No. AG020992.

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  1. New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, New York, 10314, USA

    Ved Chauhan, Lina Ji & Abha Chauhan

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  1. Ved Chauhan
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Correspondence to Ved Chauhan.

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Chauhan, V., Ji, L. & Chauhan, A. Anti-amyloidogenic, anti-oxidant and anti-apoptotic role of gelsolin in Alzheimer’s disease. Biogerontology 9, 381–389 (2008). https://doi.org/10.1007/s10522-008-9169-z

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