Skip to main content
SpringerLink
Log in
Book cover

Electrophysiology of Unconventional Channels and Pores pp 343–360Cite as

Amyloid Peptide Channels

  • Chapter

Part of the book series: Springer Series in Biophysics ((BIOPHYSICS,volume 18))

Abstract

Amyloid peptides and proteins appear to play a pathophysiologic role in amyloid diseases. Many amyloid peptides have been found to form ion channels under physiologic conditions. The channels from various diseases share common properties including heterodispersity, irreversibility, weak ionic selectivity, voltage-independent inhibition by Congo red and blockade by Zn+2. These features would make these channels likely to depolarize target cells and mitochondria, disrupt Ca+2 regulation, and deplete cellular energy stores leading to cell dysfunction and death. The failure of many anti-amyloid drugs in human clinical trials may be related to the membrane location of amyloid channels.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Abramov AY, Canevari L, Duchen MR (2004) Beta-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase. J Neurosci 24(2):565–575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Anekonda TS, Quinn JF, Harris C, Frahler K, Wadsworth TL, Woltier RL (2010) L-type voltage- Au10 gated calcium channel blockade with isradipine as a therapeutic strategy for Alzheimer’s disease. Neurobiol Dis 41:62–70. 21

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Arispe N, 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

    Article  CAS  PubMed  Google Scholar 

  • Arispe N, Rojas E, Pollard HB (1993a) Alzheimer disease amyloid beta protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminum. Proc Natl Acad Sci U S A 90(2):567–571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arispe N, Pollard HB, 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 U S A 90(22):10573–10577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arispe N, Pollard HB, Rojas E (1994) beta-Amyloid Ca(2+)-channel hypothesis for neuronal death in Alzheimer disease. Mol Cell Biochem 140(2):119–125

    Article  CAS  PubMed  Google Scholar 

  • Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S (2004) Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431(7010):805–810

    Article  CAS  PubMed  Google Scholar 

  • Azimova RK, Kagan BL (2003) Ion channels formed by a fragment of alpha-synuclein (NAC) in lipid membranes. Biophys J 84(2):53a

    Google Scholar 

  • Bahadi R, Farrelly PV, Kenna BL, Kourie JI, Tagliavini F, Forloni G et al (2003) 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 Cell Physiol 285(4):C862–C872

    Article  CAS  PubMed  Google Scholar 

  • Bekris LM, Mata IF, Zabetian CP (2010) The genetics of Parkinson disease. J Geriatr Psychiatry Neurol 23(4):228–242. Epub 2010 Oct 11. 23

    Article  PubMed  PubMed Central  Google Scholar 

  • Berest V, Rutkowski M, Rolka K, Łegowska A, Debska G, Stepkowski D et al (2003) The prion peptide forms ion channels in planar lipid bilayers. Cell Mol Biol Lett 8(2):353–362

    CAS  PubMed  Google Scholar 

  • Blaustein RO, Koehler TM, Collier RJ, Finkelstein A (1989) Anthrax toxin: channel-forming activity of protective antigen in planar phospholipid bilayers. Proc Natl Acad Sci U S A 86(7):2209–2213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Camilleri A, Zarb C, Caruana M, Ostermeier U, Ghio S, Högen T, Schmidt F, Giese A, Vassallo N (2013) Mitochondrial membrane permeabilisation by amyloid aggregates and protection by polyphenols. Biochim Biophys Acta 1828(11):2532–2543

    Article  CAS  PubMed  Google Scholar 

  • Caughey B, Lansbury PT Jr (2003) Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu Rev Neurosci 26:267–298

    Article  CAS  PubMed  Google Scholar 

  • Cobb NJ, Surewicz WK (2009) Prion diseases and their biochemical mechanisms. Biochemistry 48(12):2574–2585

    Article  CAS  PubMed  Google Scholar 

  • Cowan SW, Schirmer T, Rummel G, Steiert M, Ghosh R, Pauptit RA et al (1992) Crystal structures explain functional properties of two E coli porins. Nature 358(6389):727–733

    Article  CAS  PubMed  Google Scholar 

  • Díaz JC, Linnehan J, Pollard H, Arispe N (2006) Histidines 13 and 14 in the Abeta sequence are targets for inhibition of Alzheimer’s disease Abeta ion channel and cytotoxicity. Biol Res 39(3):447–460

    Article  PubMed  Google Scholar 

  • Diaz JC, Simakova O, Jacobson KA, Arispe N, Pollard HB (2009) Small molecule blockers of the Alzheimer Abeta calcium channel potently protect neurons from Abeta cytotoxicity. Proc Natl Acad Sci U S A 106(9):3348–3353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Durell SR, Guy HR, Arispe N, Rojas E, Pollard HB (1994) Theoretical models of the ion channel structure of amyloid beta-protein. Biophys J 67(6):2137–2145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Farrelly PV, Kenna BL, Laohachai KL, Bahadi R, Salmona M, Forloni G et al (2003) Quinacrine blocks PrP(106–126) formed channels. J Neurosci Res 74(6):934–941

    Article  CAS  PubMed  Google Scholar 

  • Fernandez A, Berry RS (2003) Proteins with H-bond packing defects are highly interactive with lipid bilayers: implications for amyloidogenesis. Proc Natl Acad Sci U S A 100:2391–2396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Forloni G, Angeretti N, Chiesa R, Monzani E, Salmona M, Bugiani O et al (1993) Neurotoxicity of a prion protein fragment. Nature 362(6420):543–546

    Article  CAS  PubMed  Google Scholar 

  • Fraser SP, Suh YH, Chong YH, Djamgoz MB (1996) Membrane currents induced in Xenopus oocytes by the C-terminal fragment of the amyloid protein (APP). J Neurochem 66(5):2034–2040

    Article  CAS  PubMed  Google Scholar 

  • Fraser SP, Suh YH, Djamgoz MB (1997) Ionic effects of the Alzheimer’s disease beta-amyloid precursor protein and its metabolic fragments. Trends J Neurosci 20:67–72

    Article  CAS  Google Scholar 

  • Garwood C, Faizullabhoy A, Wharton SB, Ince PG, Heath PR, Shaw PJ, Baxter L, Gelsthorpe C, Forster G, Matthews FE, Brayne C, Simpson JE, MRC Cognitive Function and Ageing Neuropathology Study Group (2013) Calcium dysregulation in relation to Alzheimer-type pathology in the ageing brain. Neuropathol Appl Neurobiol 39(7):788–799

    Article  CAS  PubMed  Google Scholar 

  • Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256:184–185

    Article  CAS  PubMed  Google Scholar 

  • Hegde RS, Mastrianni JA, Scott MR, DeFea KA, Tremblay P, Torchia M et al (1998) A transmembrane form of the prion protein in neurodegenerative disease. Science 279:827–834

    Article  CAS  PubMed  Google Scholar 

  • Hirakura Y, Lin MC, Kagan BL (1999) Alzheimer amyloid abeta1-42 channels: effects of solvent, pH, and Congo red. J Neurosci Res 57:458–466

    Article  CAS  PubMed  Google Scholar 

  • Hirakura Y, Azimov R, Azimova R, Kagan BL (2000) Polyglutamine-induced ion channels: a possible mechanism for the neurotoxicity of Huntington and other CAG repeat diseases. J Neurosci Res 60:490–494

    Article  CAS  PubMed  Google Scholar 

  • Inoue S (2008) In situ Abeta pores in AD brain are cylindrical assembly of Abeta protofilaments. Amyloid 15(4):223–233

    Article  CAS  PubMed  Google Scholar 

  • Jang H, Zheng J, Lal R, Nussinov R (2008) New structures help the modeling of toxic amyloidbeta ion channels. Trends Biochem Sci 33:91–100. 26

    Article  CAS  PubMed  Google Scholar 

  • Jang H, Arce FT, Capone R, Ramachandran S, Lal R, Nussinov R (2009) Misfolded amyloid ion channels present mobile beta-sheet subunits in contrast to conventional ion channels. Biophys J 97(11):3029–3037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jang H, Teran AF, Ramachandran S, Capone R, Lal R, Nussinov R (2010) Structural convergence among diverse, toxic beta-sheet ion channels. J Phys Chem B 114(29):9445–9451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jang H, Connelly L, Arce FT, Ramachandran S, Lal R, Kagan BL (2013) R Nussinov Alzheimer’s disease: which type of amyloid-preventing drug agents to employ? Phys Chem Chem Phys 15:8868–8877

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kagan BL (1983) Mode of action of yeast killer toxins: channel formation in lipid bilayer membranes. Nature 302(5910):709–711

    Article  CAS  PubMed  Google Scholar 

  • Kagan BL, Thundimadathil J (2010) Amyloid peptide pores and the beta sheet conformation. Adv Exp Med Biol 677:150–167

    Article  CAS  PubMed  Google Scholar 

  • Kagan BL, Selsted ME, Ganz T, Lehrer RI (1990) Antimicrobial defensin peptides form voltage dependent ion-permeable channels in planar lipid bilayer membranes. Proc Natl Acad Sci U S A 87:210–214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kagan BL, Azimov R, Azimova R (2004) Amyloid peptide channels. J Membr Biol 202(1):1–10

    Article  CAS  PubMed  Google Scholar 

  • Kayed R, Head E, Thompson JL, McIntire TM, Milton SC, Cotman CW et al (2003) Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300(5618):486–489

    Article  CAS  PubMed  Google Scholar 

  • Kim HS, Lee JH, Lee JP, Kim EM, Chang KA, Park CH et al (2002) Amyloid beta peptide induces cytochrome C release from isolated mitochondria. Neuroreport 13:1989–1993

    Article  CAS  PubMed  Google Scholar 

  • Kim HY, Cho MK, Kumar A, Maier E, Siebenhaar C, Becker S et al (2009) Structural properties of pore-forming oligomers of alpha-synuclein. J Am Chem Soc 131(47):17482–17489

    Article  CAS  PubMed  Google Scholar 

  • Kostka M, Högen T, Danzer KM, Levin J, Habeck M, Wirth A et al (2008) Single particle characterization of iron-induced pore-forming alpha-synuclein oligomers. J Biol Chem 283(16):10992–11003

    Article  CAS  PubMed  Google Scholar 

  • Kourie JI, Culverson A (2000) Prion peptide fragment PrP[106–126] forms distinct cation channel types. J Neurosci Res 62:120–133. 22

    Article  CAS  PubMed  Google Scholar 

  • Kourie JI, Kenna BL, Tew D, Jobling MF, Curtain CC, Masters CL et al (2003) Copper modulation of ion channels of PrP[106–126] mutant prion peptide fragments. J Membr Biol 193(1):35–45

    Article  CAS  PubMed  Google Scholar 

  • Krasilnikov OV, Sabirov RZ, Ternovsky VI, Merzliak PG, Tashmukhamedov BA (1988) The structure of Staphylococcus aureus alpha-toxin-induced ionic channel. Gen Physiol Biophys 7(5):467–473

    CAS  PubMed  Google Scholar 

  • Lazebnik Y (2001) Why do regulators of apoptosis look like bacterial toxins? Curr Biol 11(19):R767–R768

    Article  CAS  PubMed  Google Scholar 

  • Lin MC, Mirzabekov T, Kagan BL (1997) Channel formation by a neurotoxic prion protein fragment. J Biol Chem 272:44–47

    Article  CAS  PubMed  Google Scholar 

  • Lin H, Zhu YJ, Lal R (1999) Amyloid beta protein (1–40) forms calcium-permeable, Zn2+-sensitive channel in reconstituted lipid vesicles. Biochemistry 38:11189–11196

    Article  CAS  PubMed  Google Scholar 

  • Liu D, Pitta M, Lee JH, Ray B, Lahiri D, Furukawa K et al (2010) The KATP channel activator Au10 diazoxide ameliorates amyloid-b and tau pathologies and improves memory in the 3xTgAD mouse model of Alzheimer’s disease. J Alzheimers Dis 22:443–457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mirzabekov T, Lin MC, Yuan WL, Marshall PJ, Carman M, Tomaselli K et al (1994) Channel formation in planar lipid bilayers by a neurotoxic fragment of the beta-amyloid peptide. Biochem Biophys Res Commun 202:1142–1148

    Article  CAS  PubMed  Google Scholar 

  • Ng AW, Wasan KM, Lopez-Berestein G (2003) Development of liposomal polyene antibiotics: an historical perspective. J Pharm Pharm Sci 6(1):67–83

    CAS  PubMed  Google Scholar 

  • Nikaido H, Rosenberg EY, Foulds J (1983) Porin channels in Escherichia coli: studies with β-lactams in intact cells. J Bacteriol 153:232–240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Orr AL, Li S, Wang CE, Li H, Wang J, Rong J, Xu X, Mastroberardino PG, Greenamyre JT, Li XJ (2008) N-terminal mutant huntingtin associates with mitochondria and impairs mitochondrial trafficking. J Neurosci 28(11):2783–2792

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pan KM, Baldwin M, Nguyen J, Gasset M, Serban A, Groth D et al (1993) Conversion of alphahelices into beta-sheets features in the formation of the scrapie prion proteins. Proc Natl Acad Sci U S A 90:10962–10966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Panov A, Obertone T, Bennett-Desmelik J, Greenamyre JT (1999) Ca(2+)-dependent permeability transition and complex I activity in lymphoblast mitochondria from normal individuals and patients with Huntington’s or Alzheimer’s disease. Ann N Y Acad Sci 893:365–368

    Article  CAS  PubMed  Google Scholar 

  • Parks JK, Smith TS, Trimmer PA, Bennett JP Jr, Parker WD 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

    Article  CAS  PubMed  Google Scholar 

  • Quist A, Doudevski I, Lin H, Azimova R, Ng D, Frangione B et al (2005) Amyloid ion channels: a common structural link for protein-misfolding disease. Proc Natl Acad Sci U S A 102(30):10427–10432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rhee SK, Quist AP, Lal R (1998) Amyloid beta protein-(1–42) forms calcium-permeable, Zn2+sensitive channel. J Biol Chem 273:13379–13382

    Article  CAS  PubMed  Google Scholar 

  • Schein SJ, Kagan BL, Finkelstein A (1978) Colicin K acts by forming voltage-dependent channels in phospholipid bilayer membranes. Nature 276:159–163

    Article  CAS  PubMed  Google Scholar 

  • Shepard LA, Shatursky O, Johnson AE, Tweten RK (2000) The mechanism of pore assembly for a cholesterol-dependent cytolysin: formation of a large prepore complex precedes the insertion of the transmembrane beta-hairpins. Biochemistry 39(33):10284–10293

    Article  CAS  PubMed  Google Scholar 

  • Sipe JD, Cohen AS (2000) Review: history of the amyloid fibril. J Struct Biol 130:88–98

    Article  CAS  PubMed  Google Scholar 

  • Sokolov Y, Mirzabekov T, Martin DW, Lehrer RI, Kagan BL (1999) Membrane channel formation by antimicrobial protegrins. Biochim Biophys Acta 1420(1):23–29. 27

    Article  CAS  PubMed  Google Scholar 

  • Solomon IH, Huettner JE, Harris DA (2010) Neurotoxic mutants of the prion protein induce spontaneous ionic currents in cultured cells. J Biol Chem 285(34):26719–26726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Solomon IH, Biasini E, Harris DA (2012) Ion channels induced by the prion protein: mediators of neurotoxicity. Prion 6(1):40–45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Song L, Hobaugh MR, Shustak C, Cheley S, Bayley H, Gouaux JE (1996) Structure of staphylococcal alpha-hemolysin, a heptameric transmembrane pore. Science 274:1859–1866

    Article  CAS  PubMed  Google Scholar 

  • Tanford C (1980) The hydrophobic effect: formation of micelles and biological membranes. Wiley-Interscience, New York. ISBN 10: 0471048933 ISBN 13: 9780471048930

    Google Scholar 

  • Thundimadathil J, Roeske RW, Guo L (2006) Effect of membrane mimicking environment on the conformation of a pore-forming (xSxG)6 peptide. Biopolymers 84:317–328

    Article  CAS  PubMed  Google Scholar 

  • Volles MJ, Lansbury PT 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(14):4595–4602

    Article  CAS  PubMed  Google Scholar 

  • Wu N, Joshi PR, Cepeda C, Masliah E, Levine MS (2010) Alpha-synuclein overexpression in mice alters synaptic communication in the corticostriatal pathway. J Neurosci Res 88(8):1764–1776

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yankner BA, Dawes LR, Fisher S, Villa-Komaroff L, Oster-Granite ML, Neve RL (1989) Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer’s disease. Science 245(4916):417–420

    Article  CAS  PubMed  Google Scholar 

  • Zakharov SD, Hulleman JD, Dutseva EA, Antonenko YN, Rochet JC, Cramer WA (2007) Helical alpha-synuclein forms highly conductive ion channels. Biochemistry 46:14369–14379

    Article  CAS  PubMed  Google Scholar 

  • Zhu YJ, Lin H, 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(9):1244–1254

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Ms. Doris Finck for editorial assistance.

Author information

Authors and Affiliations

  1. Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Rustam Azimov & Bruce L. Kagan

Authors
  1. Rustam Azimov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bruce L. Kagan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bruce L. Kagan .

Editor information

Editors and Affiliations

  1. Department of Biology and Biochemistry, University of Houston, Houston, TX, USA

    Anne H. Delcour

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Azimov, R., Kagan, B.L. (2015). Amyloid Peptide Channels. In: Delcour, A.H. (eds) Electrophysiology of Unconventional Channels and Pores. Springer Series in Biophysics, vol 18. Springer, Cham. https://doi.org/10.1007/978-3-319-20149-8_14

Download citation

Publish with us

Policies and ethics

Search

Navigation