Skip to main content
SpringerLink
Log in

Roles of Aβ and carboxyl terminal peptide fragments of amyloid precursor protein in Alzheimer disease

  • Conference paper
Advances in Research on Neurodegeneration

  • 183 Accesses

Summary

Several lines of evidence indicate that Aβ may play an important role in the pathogenesis of AD. However, there are several discrepancies between the production of Aβ and the development of the disease.

Thus, Aβ may not be the sole active fragment of β-amyloid precursor protein (βAPP) in the neurotoxicity assiciated with AD.

We focused on the amyloidegenic carboxyl terminal fragments of βAPP containing the full length of Aβ (CT105). We synthesized a recombinant carboxyl-terminal 105 amino acid fragment of βAPP and examined the effects of CT105 and Aβ on cultured neurons, Ca++ uptake into rat brain microsomes, Na+ -Ca++ exchange activity, ion channel forming activity in lipid bilayers and passive avoidance performance of mice.

Our results suggest that the cytotoxic and channel inducing effects of CT105 are much more potent than that of Aβ and toxic mechanisms of CT105 are different from those of Aβ.

Taken together, these lines of evidence postulate that CT is an alternative toxic element important in the generation of the symptoms common to AD.

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

Access this chapter

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 39.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 54.99
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

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Similar content being viewed by others

References

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

    Article  PubMed  CAS  Google Scholar 

  • Bhadkdi S, Tranum J.J. (1987) Damage to mammalian cells by proteins that form transmembrane pores. Rev Physiol Biochem Pharmacol 107: 147–223

    Article  Google Scholar 

  • Caputo C.B., Sobel I.R., Scott C.W., Brunner W.F., Barth P.T., Blowers D.P. (1992) Association of the carboxy-terminus of beta-amyloid protein precursor with Alzheimer paired helical filaments. Biochem Biophys Res Commun 185: 1034–1040

    Article  PubMed  CAS  Google Scholar 

  • Cheder F (1995) Processing of the β-amyloid precursor protein and its regulation in Alzheimer’s disease. J Neurochem 65: 1431–1444

    Google Scholar 

  • Chung Y.H., Jung J.M., Choi W, Park C.H., Choi K.S., Suh Y.H. (1994) Bacterial expression, purification of full length and carboxy terminal fragment of Alzheimer’s precusor protein and their proteolytic processing by thrombin. Life Sci 54: 1259–1268

    Article  Google Scholar 

  • Cullen W.K., Suh Y.H., Anwyl R, Rowan M.J. (1997) Block of late-phase long-term potentiation in rat hippocampus in vivo by β-amyloid precursor protein fragments. Neuroreport 8: 3213–3217

    Article  PubMed  CAS  Google Scholar 

  • Chow N, Korenberg J.R., Chen X.N., Neve R.L. (1996) APP-BPI, a novel protein that binds to the caryboxy-teriminal region of the amyloid protein precusor. J Biol Chem 271:11339-11346

    Google Scholar 

  • Clemens J.A., Stephenson DT (1992) Implants containing beta-amyloid protein are not neurotoxic to young and old rat brain. Neurobiol Aging 13: 581–586

    Article  PubMed  CAS  Google Scholar 

  • Drake L, Korchev Y, Bashford L, Djamgoz M, Wakelin D, Ashall F, Bundy D (1994) The major secreted product of the whipworm, Trichuris, is a pore-forming protein. Proc R Soc Lond [Biol] 257: 255–261

    Article  CAS  Google Scholar 

  • Duffy P.E., Rapport M, Graf L (1980) Glial fibrillary acidic protein and Alzheimer-type senile dementia. Neurology 30: 778–782

    Article  PubMed  CAS  Google Scholar 

  • Dyrks T, Dyrks E, Hartmann T, Masters C, Bryreuther K (1992) Amyloidogenicity of βA4 and βA4-bearing amyloid protein precursor fragments by metal-catalyzed oxidation. J Biol Chem 267: 18210–18217

    PubMed  CAS  Google Scholar 

  • Edelman A.M., Hunter D.D., Hendrickson A.E., Krebs E.G. (1985) Subcellular distribution of calcium- and calmodulin-dependent myosin light chain phosphorylating activity in rat cerebral cortex. J Neurosci 5(10): 2609–2617

    PubMed  CAS  Google Scholar 

  • Estus S, Coide T.E., Kunishita T.L., Blades D, Lowery D, Eisen J, Usiak M, Tabira T.L., Greenberg B.D., Younkin S.G. (1992) Potentially amyloidogenic, carboxyl-terminal derivatives of the amyloid protein precursor. Science 255: 726–728

    Article  PubMed  CAS  Google Scholar 

  • Fraser S, Suh Y.H., Chong Y.H., Djamgoz M.A. (1996) Membrane currents induced in Xenopus oocytes by the carboxyl terminal fragment of the β-amyloid precursor protein. J Neurochem 66: 2034–2040

    Article  PubMed  CAS  Google Scholar 

  • Fraser S.P., Suh Y.H., Djamgoz M.B.A. (1997) Ionic effects of the Alzheimer’s disease βamyloid precursor protein and its metabolic fragments. Trends Neurosci 20: 67–72

    Article  PubMed  CAS  Google Scholar 

  • Fukuchi K, Kamino K, Deeb S.S., Furlong C.E., Sundstrom J.A., Smith A.C., Martin G.M. (1992) Expression of a carboxy-terminal region of the beta-amyloid precursor protein in a heterogeneous culture of neuroblastoma cells: evidence for altered processing and selective neurotoxicity. Mol Brain Res 16: 37–46

    Article  PubMed  CAS  Google Scholar 

  • Fukuchi K, Sopher B, Martin G.M. (1993a) Neurotoxicity of beta-amyloid. Nature 361:122–123

    Article  PubMed  CAS  Google Scholar 

  • Fukuchi K, Sopher B, Furlong C.E., Smith A.C., Dnag T, Martin G.M. (1993b) Selective neurotoxicity of COOH-terminal fragments of the beta-amyloid precursor protein in mouse brains by transplantation of transformed neuronal cells. Exp Neurol 127: 253–264

    Article  Google Scholar 

  • Fukuchi K, Kunkel D.D., Schwartzkroin P.A., Kamino K, Ogburn C.E., Furlong C.E., Martin G.M. (1994) Overexpression of a C-terminal portion of the beta-amyloid precursor protein in mouse brains by transplantation of transformed neuronal cells. Exp Neurol 127:253–264

    Article  PubMed  CAS  Google Scholar 

  • Games D, Khan K.M., Soriano F.G., Keirn P.S., Davis D.L., Bryant K, Lieberburg I (1992) Lack of Alzheimer’s pathology after β-amyloid protein injections in rat brain.Neurobiol Aging 13: 569–576

    Article  PubMed  CAS  Google Scholar 

  • Glenner G.G., Wong C.W. (1984) Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 120: 885–890

    Article  PubMed  CAS  Google Scholar 

  • Golde T.E., Estus S, Younkin L.H., Selkoe D.J., Younkin S.G. (1992) Processing of the amyloid protein precursor to potentially amyloidogenic derivatives. Sciences 255:728–730

    Article  CAS  Google Scholar 

  • Hartell N.A., Suh Y.H., Lee K.W. (1996) Effects of peptide fragments of APP on parallel fiber-purkinje cell synaptic transmission in rat cerebellum. Degenerative disease: Alzheimer’s Beta-Amyloid-Membrane Interactions. 26th Annual Meeting of Society for Neuroscience, Washington 1996, Abstract 22 (Part 3): p 2110

    Google Scholar 

  • Kametani F, Tanaka K, Tokuda T, Ikeda S (1994) Secretory cleavage site of Alzheimer amyloid precursor protein in heterogeneous in Down’s syndrome brain. FEBS Lett 351: 165–167

    Article  PubMed  CAS  Google Scholar 

  • Kammeshidt A, Boyce F.M., Spanoyannis A.F., Cummings B.J., Ortegon J, Cotman C, Vaught J.L., Neve R.L. (1992) Desposition of beta/A4 immunoreactivity and neuronal pathology in transgenic mice expressing the carboxyl-terminal fragment of the Alzheimer amyloid precursor in the brain. Proc Natl Acad Sci USA 89: 10857–10861

    Article  Google Scholar 

  • Kang J, Lemaire H.G., Unterbeck A, Salbaum M.N., Masters C.L., Grzeschik K.H., Multhaup C, Beyreuther K, Muller-Hill B (1987) The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell surface receptor. Nature 325: 733–736

    Article  PubMed  CAS  Google Scholar 

  • Kijima Y, Ogunbummi E, Fleischer S (1991) Drug action of thapsigargin on the Ca2+ pump protein of Sarcoplasmic reticulum. J Biol Chem 266(34): 22912–22918

    PubMed  CAS  Google Scholar 

  • Kim H.J., Suh Y.H., Lee M.H., Ryu P.D. (1996) C-terminal fragment of the β amyloidal precursor protein forms cation selective channels in planar lipid bilayer. Degenerative disease: Alzheimer’s Beta-Amyloid-Membrane Interactions. 26th Annual Meeting of Society for Neuroscience, Washington 1996, Abstract 22 (Part 3): p 2110

    Google Scholar 

  • Kim S.H., Suh Y.H. (1996) Neurotoxicity of a caroboxy teiminal fragment of the Alzheimer’s amyloid precursor protein. J Neurochem 67: 1172–1182

    Article  PubMed  CAS  Google Scholar 

  • Kozlowski M.R., Spanoyannis A.L., Manly S.P., Fidel S.A., Neve R.L. (1992) The neurotoxic carboxy-terminal fragment of the Alzheimer amyloid precursor binds specifically to a neuronal cell surface molecule: pH dependence of the neurotoxicity and the binding. J Neurosci 12: 1679–1687

    PubMed  CAS  Google Scholar 

  • Laursen S.E., Belknap J.K. (1986) Intracerebroventricular injections in mice. Some methodolegical refinements. J Pharmacol Methods 16: 355–357

    Article  PubMed  CAS  Google Scholar 

  • Leyser H.M.O., Lincoln C.A., Timpte C, Lammer D, Turner J, Estelle M (1993) Arabidopsis auxin-resistance gene AXR1 encodes a protein related to ubiquitin-activating enzyme E1. Nature 364: 161–164

    Article  PubMed  CAS  Google Scholar 

  • Matsumoto A (1994) Altered processing characteristics of amyloid-coataining peptides in cytosol and media of familial Alzheime’s disease cells. Biochem Biophys Acta 1225:304–310

    Article  PubMed  CAS  Google Scholar 

  • Matsumoto A, Matsumoto R (1994) Familial Alzheimer’s disease cells abnormal abnormally accumulate beta-amyloid harbouring peptides preferentially in cytosol but not in extracellar fluid. Eur J Biochem 225: 1055–1062

    Article  PubMed  CAS  Google Scholar 

  • McPhie D.L., Lee R.K.K., Eckman C.B., Olstein D.H., Durham S.P., Yager D, Younkin S.G., Wurtman R.J., Neve R.L. (1997) Neuronal expression of beta-amyloid precursor protein Alzheimer mutations causes intracellular accumulation of a C-terminal fragment containing both the amyloid beta and cytoplasmic domains. J Biol Chem 272(40):24743–24746

    Article  PubMed  CAS  Google Scholar 

  • Nalbantoglu J, Tirado-Santiago G, Lahsaini A, Poirier J, Gonocalves O, Verge G, Momoli F, Weiner S.A., Massicotte G, Jullien J.P., Shapiro M.L. (1997) Impaired learning and LTP in mice expressing the carboxy terminus of the Alzheimer amyloid precursor protein. Nature 387: 500–505

    Article  PubMed  CAS  Google Scholar 

  • Palade P, Dettbarn C, Volpe P, Alderson B, Otero A.S. (1989) Direct inhibition of inositol-1,4,5-trisphosphate-induced Ca2+ release from brain microsomes by K+ channel blockers. Mol Pharmacol 36(4): 664–672

    PubMed  CAS  Google Scholar 

  • Pike C.J., Cummings B.J., Cotman C.W. (1995) Early association of reactive astrocytes with senile palques in Alzheimer’s disease. Exp Neurol 132: 172–179

    Article  PubMed  CAS  Google Scholar 

  • Podlisny M.B., Stephenson D.T., Frosch M.P., Tolan D.R., Lieberburg I, Clemens JA, Selkoe DJ (1993) Microinjection of synthetic amyloid beta-protein monkey cerebral cortex fails to produce acute neurotoxicity. Am J Pathol 142: 17–24

    PubMed  CAS  Google Scholar 

  • Potter H (1992) The involvement of astrocytes and an acute phase response in the amyloid deposition of Alzheimer’s disease. Prog Brain Res 94: 447–458

    Article  PubMed  CAS  Google Scholar 

  • Selkoe D.J. (1994) Alzheimer’s disease: a central role for amyloid. J Neuropathol Exp Neurosci 60: 607–619

    Google Scholar 

  • Selkoe D.J., Podlisny M.B., Joachim C.L., Vickers E.A., Lee G, Friz LC, Oltersdorf T (1988) Beta-amyloid precursor protein of Alzheimer disease occurs as 110- to 135-kilodalton membrane-associated proteins in neuronal and nonneural tissues. Proc Natl Acad Sci USA 85: 7341–7345

    Article  PubMed  CAS  Google Scholar 

  • Shearman M.S., Hawtin S.R., Tailor V.J. (1995) The intracellular component of cellular 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction is specifically inhibited by beta-amyloid peptides. J Neurochem 65(1): 218–227

    Article  PubMed  CAS  Google Scholar 

  • Song D.K., Won M.H., Jung J.S., Lee J.C., Kang T.C., Suh H.W., Huh S.O., Paek S.H., Kim Y.H., Kim S.H., Suh Y.H. (1998) Behavioral and neuropathologic changes induced by central injection of carboxyl-terminal fragment of beta-amyloid precursor protein in mice. J Neurochem 71(2): 875–878

    Article  PubMed  CAS  Google Scholar 

  • Sopher B.L., Fukuchi K, Smith A.C., Leppig K.A., Furlong C.E., Martin G.M. (1994) Cytotoxicity mediated by conditional expression of a carboxyl-terminal derivative of the betaamyloid precursor protein. Mol Brain Res 26: 207–217

    Article  PubMed  CAS  Google Scholar 

  • Stein B.B., Adams K, Yeh M, Sapolsky R (1992) Failure of beta-amyloid protein fragment 25-35 to cause hippocaupal damage in the rat. Neurobiol Aging 13: 577–579

    Article  Google Scholar 

  • Suh Y.H. (1997) An etiological role of amyloidogenic carbosyl-terminal fragments of the β-amyloid precursor protein in Alzheimer’s disease. J Neurochem 68: 1781–1791

    Article  PubMed  CAS  Google Scholar 

  • Suh Y.H., Chong Y.H., Kim S.H., Choi W, Kim K.S., Jeong S.J., Fraser S.P., Djamgoz M.B.A. (1996) Molecular physiology, biochemistry, and pharmacology of Alzheimer’s amyloid precursor protein (APP). Ann NY Acad Sci 786: 169–183

    Article  PubMed  CAS  Google Scholar 

  • Tamaoka A, Kalaria R.N., Lieberburg I, Selkoe D.J. (1992) Identification of a stable fragment of the Alzheimer amyloid precursor contataining the beta-protein in brain microvessels. Proc Natl Sci USA 89: 1345–1349

    Article  CAS  Google Scholar 

  • Tokuda T, Tanaka K, Kametani F, Ikeda S, Yanagisawa N (1995) Seceretory cleavage of beta-amyloid precursor protein in the cerebral white matter produces amyloidogenic carboxyl-terminal fragments. Neurosci Lett 186: 149–152

    Article  PubMed  CAS  Google Scholar 

  • Wisniewski H.M., Wegiel J (1991) Spatial relationships beween astrocytes and classical plaque components. Neurobiol Aging 12: 593–600

    Article  PubMed  CAS  Google Scholar 

  • Wolf D, Quon D, Wang Y, Cordell B (1990) Identification and characterzation of C-terminal fragments of the amyloid β/A4 protein precursor produced in cell culture. EMBO J 9: 2079–2084

    PubMed  CAS  Google Scholar 

  • Yankner B.A., Dawes L.R., Fisher S, Villa Komaroff L, Oster Granite M.L., Neve R.L. (1989) Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer’s disease. Science 245: 417–420

    Article  PubMed  CAS  Google Scholar 

  • Yankner B.A., Duffy L.K., Kirschner D.A. (1990) Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Science 250: 279–282

    Article  PubMed  CAS  Google Scholar 

  • Yoshikawa K, Aizawa T, Hayashi Y (1992) Degeneration in vitro of post-mitotic neurons overexpressing the Alzheimer amyloid protein precursor. Nature 359: 64–67

    Article  PubMed  CAS  Google Scholar 

  • Young J.D., Peterson C.G., Venge P, Cohn Z.A. (1986) Mechanism of membrane damage mediated by human eosinophil cationic protein. Nature 321: 613–616

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, College of Medicine, Seoul National University, 28 Yongon-dong, Chongno-gu, Seoul, 110-799, Korea

    Y.-H. Suh MD, Ph.D., H.-S. Kim, J. P. Lee, C. H. Park, S.-J. Jeong, J.-C. Rah & J.-H. Seo

  2. Department of Pharmacology, College of Medicine, Kang Won National University, Seoul, Korea

    S.-S. Kim

  3. Department of Anatomy, College of Medicine, Chung Ang University, Seoul, Korea

    S.-S. Kim

  4. Biomedical Brain Research Center, NIH, Seoul, Korea

    Y.-H. Suh MD, Ph.D., H.-S. Kim, J. P. Lee, C. H. Park, S.-J. Jeong, J.-C. Rah & J.-H. Seo

Authors
  1. Y.-H. Suh MD, Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H.-S. Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. P. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C. H. Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S.-J. Jeong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S.-S. Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J.-C. Rah
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J.-H. Seo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. S.-S. Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan

    Y. Mizuno

  2. Neurodegenerative Disorders Centre, Faculty of Medicine, University Hospital, Vancouver, B.C., Canada

    D. B. Calne

  3. Clinical Research, Schering AG, Berlin, Federal Republic of Germany

    R. Horowski

  4. Department of Neurology, University of Innsbruck, Austria

    W. Poewe

  5. Department of Psychiatry, University of Würzburg, Federal Republic of Germany

    P. Riederer

  6. Rappaport Family Institute for Research in the Medical Sciences, Haifa, Israel

    M. B. H. Youdim

Rights and permissions

Reprints and permissions

Copyright information

© 2000 Springer-Verlag Wien

About this paper

Cite this paper

Suh, YH. et al. (2000). Roles of Aβ and carboxyl terminal peptide fragments of amyloid precursor protein in Alzheimer disease. In: Mizuno, Y., Calne, D.B., Horowski, R., Poewe, W., Riederer, P., Youdim, M.B.H. (eds) Advances in Research on Neurodegeneration. Springer, Vienna. https://doi.org/10.1007/978-3-7091-6284-2_6

Download citation

  • DOI: https://doi.org/10.1007/978-3-7091-6284-2_6

  • Publisher Name: Springer, Vienna

  • Print ISBN: 978-3-7091-7246-9

  • Online ISBN: 978-3-7091-6284-2

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation