Abstract
A plethora of clinical syndromes are characterized by the deposition of amorphous, Congo red staining material known as “amyloid.” These protein folding diseases include Alzheimer’s, Parkinson’s, type II diabetes mellitus, rheumatoid arthritis, and “mad cow” disease. Amyloid-forming peptides readily adapt beta-sheet structure and can spontaneously aggregate into extended fibrils despite having no primary sequence homology. All amyloid peptides appear to interact strongly with lipid membranes, assemble into oligomers, and form ion-permeable channels. These channels are large, heterogeneous, nonselective, and irreversible. They are inhibited by Congo red and blocked by Zn+2. The leakage pathway induced by these channels could be responsible for the cellular pathology of amyloidoses, including membrane depolarization, mitochondrial dysfunction, inhibition of long-term potential (LTP), and cytotoxicity. We suggest that channel formation underlies amyloid disease.
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References
Abramov, A.Y., Canevari, L., and Duchen, M.R. (2004). Beta-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase. J. Neurosci. 24:565–575.
Anguiano, M., Nowak, R.J., and Lansbury, P.T., Jr. (2002). Protofibrillar islet amyloid polypeptide permeabilizes synthetic vesicles by a pore-like mechanism that may be relevant to type II diabetes. Biochemistry 41(38):11338–11343.
Arispe, N. (2004). Architecture of the Alzheimer’s A beta P ion channel pore. J. Membr. Biol. 197:33–48.
Arispe, N., and Doh, M. (2002). Plasma membrane cholesterol controls the cytotoxicity of Alzheimer’s disease AbetaP (1-40) and (1-42) peptides. FASEB J. 16:1526–1536.
Arispe, N., Rojas, E., and Pollard, H.B. (1993a). Alzheimer disease amyloid beta protein forms calcium channels in bilayer membranes: blockade by tromethamine and alminum. Proc. Natl. Acad. Sci. USA 90(1):567–571.
Arispe, N., Pollard, H.B., and Rojas, E. (1993b). Giant multilevel cation channels formed by Alzheimer disease amyloid beta-protein [A beta P-(1-40)] in bilayer membranes. Proc. Natl. Acad. Sci. USA 90:10573–10577.
Arispe, N., Pollard, H.B., and Rojas, E. (1996). Zn2+ interaction with Alzheimer amyloid beta protein calcium channels. Proc. Natl. Acad. Sci. USA 93:1710–1715.
Bahadi, R., Farrelly, P.V., Kenna, B.L., Curtain, C.C., Masters, C.L., Cappai, R., Barnham, K.J., and Kourie, J.I. (2003a). Cu2+-induced modification of the kinetics of A beta(1-42) channels. Am. J. Physiol. 285:C873–C880.
Bahadi, R., Farrelly, P.V., Kenna, B.L., Kourie, J.I., Tagliavini, F., Forloni. G., and Salmona, M. (2003b). Channels formed with a mutant prion protein PrP(82–146) homologous to a 7-kDa fragment in diseased brain of GSS patients. Am. J. Physiol 285:C862–C872.
Bucciantini, M., Calloni, G., Chiti, F., Formigli, L, Nosi, D., Dobson, C.M., and Stefani, M. (2004). Prefibrillar amyloid protein aggregates share common features of cytotoxicity. J. Biol. Chem. 279:31374–31382.
Butler, A.E., Janson, J., Soeller, W.C., and Butler P.C. (2003). Increased beta-cell apoptosis prevents adaptive increase in beta-cell mass in mouse model of type 2 diabetes: evidence for role of islet amyloid formation rather than direct action of amyloid. Diabetes 52:2304–2314.
Caughey, B., and Lansbury, P.T., Jr. (2003). Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu. Rev. Neurosci. 26:267–298.
Chen, Q.S., Kagan, B.L., Hirakura, Y., and Xie, C.W. (2000). Impairment of hippocampal long-term potentiation by Alzheimer amyloid beta-peptides. J. Neurosci. Res. 60:65–72.
Cowan, S.W., Schirmer, T., Rummel, G., Steiert, M., Ghosh, R., Pauptit, R.A., Jansonius, J.N., and Rosenbusch, J.P. (1992). Crystal structures explain functional properties of two E. coli porins. Nature 358:727–733.
De Gioia, L., Selvaggini, C., Ghibaudi, E., Diomede, L., Bugiani, O., Forloni, G., Tagliavini, F., and Salmona, M. (1994). Conformational polymorphism of the amyloidogenic and neurotoxic peptide homologous to residues 106–126 of the prion protein. J. Biol. Chem. 269:7859–7862.
Durell, S.R., Guy, H.R., Arispe, N., Rojas, E., and Pollard, H.B. (1994). Theoretical models of the ion channel structure of amyloid beta-protein. Biophys. J. 67:2137–2145.
Farrelly, P.V., Kenna, B.L., Laohachai, K.L., Bahadi, R., Salmona, M., Forloni, G. and Kourie, J.I. (2003). Quinacrine blocks PrP (106–126)-formed channels. J. Neurosci. Res. 74:934–941.
Forloni, G., Chiesa, R., Smiroldo, S., Verga, L., Salmona, M., Tagliavini, F., and Angeretti, N. (1993). Apoptosis mediated neurotoxicity induced by chronic application of beta amyloid fragment 25–35. Neuroreport 4:523–526.
Fraser, S.P., Suh, Y.H., Chong, Y.H., and Djamgoz, M.G. (1996). Membrane currents induced in Xenopus oocytes by the C-terminal fragment of the beta-amyloid precursor protein. J. Neurochem. 66(5):2034–2040.
Furukawa, K., Abe, Y., and Akaike, N., (1994). Amyloid beta protein-induced irreversible current in rat cortical neurones. Neuroreport 5:2016–2018.
Harroun, T.A., Bradshaw, J.P., and Ashley, R.H. (2001). Inhibitors can arrest the membrane activity of human islet amyloid polypeptide independently of amyloid formation. FEBS Lett. 507:200–204.
Hegde, R.S., Mastrianni, J.A., Scott, M.R., DeFea, K.A., Tremblay, P., Torchia, M., DeArmond, S.J., Prusiner, S.B., and Lingappa, V.R. (1998). A transmembrane form of the prion protein in neurodegenerative disease. Science 279:827–834.
Hirakura, Y., and Kagan, B.L. (2001). Pore formation by beta-2-microglobulin: a mechanism for the pathogenesis of dialysis associated amyloidosis. Amyloid 8:94–100.
Hirakura, Y., Lin, M.C., and Kagan, B.L. (1999). Alzheimer amyloid abeta1-42 channels: effects of solvent, pH, and Congo Red. J. Neurosci. Res. 57:458–466.
Hirakura, Y., Azimov, R., Azimova, R., and Kagan, B.L. (2000). Polyglutamine-induced ion channels: a possible mechanism for the neurotoxicity of Huntington and other CAG repeat diseases. J. Neurosci. Res. 60:490–494.
Hirakura, Y., Azimova, R., Azimov, R., and Kagan, B.L. (2001). Ion channels with different selectivity formed by transthyretin. Biophys. J. 80–120.
Hirakura, Y., Carreras, I., Sipe, J.D., and Kagan B.L. (2002). Channel formation by serum amyloid A: a potential mechanism for amyloid pathogenesis and host defense. Amyloid 9:13–23.
Hsia, A.Y., Masliah, E., McConlogue, L., Yu, G.Q., Tatsuno, G., Hu, K., Kholodenko, D., Malenka, R.C., Nicoll, R.A., and Mucke, L. (1999). Plaque-independent disruption of neural circuits in Alzheimer’s disease mouse models. Proc. Natl. Acad. Sci. USA 96:3228–3233.
Janson, J., Ashley, R.H., Harrison, D., McIntyre, S., and Butler, P.C. (1999). The mechanism of islet amyloid polypeptide toxicity is membrane disruption by intermediate-sized toxic amyloid particles. Diabetes 48:491–498.
Janson, J., Laedtke, T., Parisi, J.E., O’Brien P., Petersen R.C., and Butler, P.C. (2004). Increased risk of type 2 diabetes in Alzheimer disease. Diabetes 53:474–481.
Kagan, B.L., Selsted, M.E., Ganz, T., and Lehrer, R.I. (1990). Antimicrobial defeusin peptides form voltage dependent ion permeable channels in planar lipid bilayer membranes. Proc. Natl. Acad. Sci. USA 87:210–214.
Kagan, B.L., Azimova, R.K. (2003). Ion channels formed by a fragment of alpha-synuclein (NAC) in lipid membranes, Biophs. J. 84(2):53a.
Kawahara, M., Arispe, N., Kuroda, Y., and Rojas, E. (1997). Alzheimer’s disease amyloid beta-protein forms Zn(2+)-sensitive, cation-selective channels across excised membrane patches from hypothalamic neurons. Biophys. J. 73:67–75.
Kawahara, M., Kuroda, Y., Arispe, N., and Rojas, E. (2000). Alzheimer’s beta-amyloid, human islet amylin, and prion protein fragment evoke intracellular free calcium elevations by a common mechanism in a hypothalamic GnRH neuronal cell line. J. Biol. Chem. 275:14077–14083.
Kim H.J., Suh, Y.H., Lee, M.H., and Ryu, P.D., (1999). Cation selective channels formed by a C-terminal fragment of beta-amyloid precursor protein. Neuroreport 14,(10)7:1427–1431.
Kim, H.S., Lee, J.H., Lee, J.P., Kim, E.M., Chang, K.A., Park, C.H., Jeong, S.J., Wittendorp, M.C., Seo, J.H., Choi, S. H., and Suh, Y.H. (2002). Amyloid beta peptide induces cytochrome c release from isolated mitochondria. Neuroreport 13:1989–1993.
Knauer, M.F., Soreghan, B., Burdick, D., Kosmoski, J., and Glabe, C.G. (1992). Intracellular accumulation and resistance to degradation of the Alzheimer amyloid A4/beta protein. Proc. Natl. Acad. Sci. USA 89:7437–7441.
Kourie, J.I. (1999). Characterization of a C-type natriuretic peptide (CNP-39)-formed cation-selective channel from platypus (Ornithorhynchus anatinus) venom. J. Physiol. 518 (Pt 2):359–369.
Kourie, J.I., and Culverson. A. (2000). Prion peptide fragment PrP[106–126] forms distinct cation channel types. J. Neurosci. Res. 62:120–133.
Kourie, J.I., Henry, C.L., and Farrelly, P. (2001). Diversity of amyloid beta protein fragment [1-40]-formed channels. Cell. Mol. Neurobiol. 21:255–284.
Kourie, J.I., Culverson, A.L., Farrelly, P.V., Henry, C.L., and Laohachai, K.N. (2002). Heterogeneous amyloid-formed ion channels as a common cytotoxic mechanism: implications for therapeutic strategies against amyloidosis. Cell Biochem. Biophys. 36:191–207.
Kourie, J.I., Kenna, B.L., Tew, D., Jobling, M.F., Curtain, C.C., Masters, C.L., Barnham, K.J., and Cappai, R. (2003). Copper modulation of ion channels of PrP[106–126] mutant prion peptide fragments. J. Membr. Biol. 193:35–45.
Larson, J., Lynch, G., Games, D., and Seubert, P. (1999). Alterations in synaptic transmission and long-term potentiation in hippocampal slices from young and aged PDAPP mice. Brain Res. 840:23–35.
Lashuel, H.A., Petre, B.M., Wall, J., Simon, M., Nowak, R.J., Walz, T., and Lansbury, P.T., Jr. (2002). Alpha-synuclein, especially the Parkinson’s disease-associated mutants, forms pore-like annular and tubular protofibrils. J. Mol. Biol. 322:1089–1102.
Lashuel, H.A., Hartley, D.M., Petre, B.M., Wall, J.S., Simon, M.N., Walz, T., and Lansbury, P.T., Jr. (2003). Mixtures of wild-type and a pathogenic (E22G) form of Abeta40 in vitro accumulate protofibrils, including amyloid pores. J. Mol. Biol. 332:795–808.
Li, S.H., and Li, X.J. (2004). Huntingtin-protein interactions and the pathogenesis of Huntington’s disease. Trends Genet. 20:146–154.
Lin, M.C., and Kagan, B.L. (2002). Electrophysiologic properties of channels induced by Abeta25-35 in planar lipid bilayers. Peptides 23:1215–1228.
Lin, M.C., Mirzabekov, T., and Kagan, B.L. (1997). Channel formation by a neurotoxic prion protein fragment. J. Biol. Chem. 272:44–47.
Lin, H., Zhu, Y.J., and Lal, R. (1999). Amyloid beta protein (1-40) forms calcium-permeable, Zn2+-sensitive channel in reconstituted lipid vesicles. Biochemistry 38:11189–11196.
Lorenzo, A., Razzaboni, B., Weir, G.C., and Yankner, B.A. (1994). Pancreatic islet cell toxicity of amylin associated with type-2 diabetes mellitus. Nature 368:756–760.
Mattson M.P., Barger S.W., Cheng B., Lieberburg I., Smith-Swintosky V.L., and Rydel R.E. (1993). beta-Amyloid precursor protein metabolites and loss of neuronal Ca2+ homeostasis in Alzheimer’s disease. Trends Neurosci. 16:409–414.
McKeith, I., Mintzer, J., Aarsland, D., Burn, D., Chiu, H., Cohen-Mansfield, J., Dickson, D., Dubois, B., Duda, J.E., Feldman, H., Gauthier, S., Halliday, G., Lawlor, B., Lippa, C., Lopez, O.L., Carlos Machado, J., O’Brien, J., Playfer, J., and Reid, W. (2004). Dementia with Lewy bodies. Lancet Neurol. 3:19–28.
Merlini G., and Bellotti V. (2003). Molecular mechanisms of amyloidosis. N. Engl. J. Med. 349:583–596.
Micelli, S., Meleleo, D., Picciarelli, V., and Gallucci, E. (2004). Effect of sterols on beta-amyloid peptide (AbetaP 1-40) channel formation and their properties in planar lipid membranes. Biophys. J. 86:2231–2237.
Mirzabekov, T., Lin, M.C., Yuan, W.L., Marshall, P.J., Carman, M., Tomaselli, K., Lieberburg, I., and Kagan, B.L. (1994). Channel formation in planar lipid bilayers by a neurotoxic fragment of the beta-amyloid peptide. Biochem. Biophys. Res. Commun. 202:1142–1148.
Mirzabekov, T.A., Lin, M.C., and Kagan, B.L. (1996). Pore formation by the cytotoxic islet amyloid peptide amylin. J. Biol. Chem. 271:1988–1992.
Moechars, D., Lorent, K., and Van Leuven, F. (1999). Premature death in transgenic mice that overexpress a mutant amyloid precursor protein is preceded by severe neurodegeneration and apoptosis. Neuroscience 91:819–830.
Monoi, H., Futaki, S., Kugimiya, S., Minakata, H., and Yoshihara, K. (2000). Poly-L-glutamine forms cation channels: relevance to the pathogenesis of the polyglutamine diseases [see comments]. Biophys. J. 78:2892–2899.
Ng, A.W., Wasan, K.M., and Lopez-Berestein, G. (2003). Development of liposomal polyene antibiotics: an historical perspective. J. Pharm. Pharm. Sci. 6:67–83.
Pan, K.M., Baldwin, M., Nguyen, J., Gasset, M., Serban, A., Groth, D., Mehlhorn, I., Huang, Z., Fletterick, R.J., and Cohen, F.E. (1993). Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins. Proc. Natl. Acad. Sci. USA 90:10962–10966.
Panov, A.V., Gutekunst, C.A., Leavitt, B.R., Hayden, M.R., Burke, J.R., Strittmatter, W.J., and Greenamyre, J.T. (2002). Early mitochondrial calcium defects in Huntington’s disease are a direct effect of polyglutamines. Nat. Neurosci. 5:731–736.
Parks, J.K., Smith, T.S., Trimmer, P.A., Bennett, J.P., Jr., and Parker, W.D., Jr. (2001). Neurotoxic Abeta peptides increase oxidative stress in vivo through NMDA-receptor and nitric-oxide-synthase mechanisms, and inhibit complex IV activity and induce a mitochondrial permeability transition in vitro. J. Neurochem. 76:1050–1056.
Ramachandran, R., Tweten, R.K., and Johnson, A.E. (2004). Membrane-dependent conformational changes initiate cholesterol-dependent cytolysin oligomerization and intersubunit beta-strand alignment. Nat. Struct. Mol. Biol. Epub 2004 July 04.
Reed, J.C. (2000). Mechanisms of apoptosis. Am. J. Pathol. 157:1415–1430.
Relini, A., Torrassa, S., Rolandi, R., Gliozzi, A., Rosano, C., Canale, C., Bolognesi, M., Plakoutsi, G., Bucciantini, M., Chiti, F., and Stefani, M. (2004). Monitoring the process of HypF fibrillization and liposome permeabilization by protofibrils. J. Mol. Biol. 338:943–957.
Rodriguez, C.M., Sola, S., Silva, R., and Brites, D. (2000). Bilirubin and amyloid-beta peptide induce cytochrome c release through mitochondrial membrane permeabilization. Mol. Med. 6(11):936–946.
Ryou, C., Legname, G., Peretz, D., Craig, J.C., Baldwin, M.A., and Prusiner, S.B. (2003). Differential inhibition of prion propagation by enantiomers of quinacrine. Lab. Invest. 83(6):837–843.
Sandberg, M.K., Wallen, P., Wikstrom, M.A., and Kristensson, K. (2004). Scrapie-infected GT1-1 cells show impaired function of voltage-gated N-type calcium channels (Ca(v) 2.2) which is ameliorated by quinacrine treatment. Neurobiol. Dis. 15:143–151.
Sanderson, K.L., Butler, L., and Ingram, V.M. (1997). Aggregates of a beta-amyloid peptide are required to induce calcium currents in neuron-like human teratocarcinoma cells: relation to Alzheimer’s disease. Brain Res. 744:7–14.
Schein, S.J., Kagan, B.L., and Finkelstein, A. (1978). Colicin K acts by forming voltage-dependent channels in phospholipids bilayer membranes. Nature 276:159–163.
Selkoe, D.J. (2002). Alzheimer’s disease is a synaptic failure. Science 298:789–791.
Simmons, M.A., and Schneider, C.R. (1993). Amyloid beta peptides act directly on single neurons. Neurosci. Lett. 150(2):133–136.
Sipe, J.D. (2000). Serum amyloid A: from fibril to function. Current status. Amyloid 7:10–12.
Sipe, J.D., and Cohen, A.S. (2000). Review: history of the amyloid fibril. J. Struct. Biol. 130:88–98.
Sokolov, Y., Mirzabekov T., Martin, D.W., Lehrer, R.I., and Kagan, B.L. (1999). Membrane channel formation by antimicrobial protegrins. Biochim. Biophys. Acta 1420:23–29.
Song, L., Hobaugh, M.R., Shustak, C., Cheley, S., Bayley, H., and Gouaux, J.E. (1996). Structure of staphylococcal alphahemolysin, a heptameric transmembrane pore. Science 274:1859–1866.
Soto, C. (2003). Unfolding the role of protein misfolding in neurodegenerative diseases. Nat. Rev. Neurosci. 4(1): 49–60.
Stipani, V., Galluci, E., Micelli, S., Picciarelli, V., and Benz, R. (2001). Channel formation by salmon and human calcitonin in black lipid membranes. Biophys. J. 81(6):3332–3338.
Volles, M.J., and Lansbury, P.T., Jr. (2002). Vesicle permeabilization by protofibrillar alpha-synuclein is sensitive to Parkinson’s disease-linked mutations and occurs by a pore-like mechanism. Biochemistry 41:4595–4602.
Walsh, D.M., Klyubin, I., Fadeeva, J.V., Cullen, W.K., Anwyl, R., Wolfe, M.S., Rowan, M.J., and Selkoe, D. J. (2002). Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416:535–539.
Westermark, P., and Wilander, E. (1978). The influence of amyloid deposits on the islet volume in maturity onset diabetes mellitus. Diabetologia 15:417–421.
Zhu, Y.J., Lin H., and Lal, R. (2000). Fresh and nonfibrillar amyloid beta protein(1-40) induces rapid cellular degeneration in aged human fibroblasts: evidence for AbetaP-channel-mediated cellular toxicity. FASEB J. 14:1244–1254.
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Kagan, B.L. (2006). Protein Aggregation, Ion Channel Formation, and Membrane Damage. In: Uversky, V.N., Fink, A.L. (eds) Protein Misfolding, Aggregation, and Conformational Diseases. Protein Reviews, vol 4. Springer, Boston, MA. https://doi.org/10.1007/0-387-25919-8_11
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