Skip to main content
SpringerLink
Log in

Alzheimer’s Disease and Hemorrhagic Stroke: Their Relationship to βA4 Amyloid Deposition

  • Conference paper
Book cover Alzheimer’s Disease: Lessons from Cell Biology

Part of the book series: Research and Perspectives in Alzheimer’s Disease ((ALZHEIMER))

Summary

Distinct mutations have been reported in approximately 5% of early-onset Alzheimer disease (AD) families in the gene coding for the amyloid precursor protein (APP) located at chromosome 21q21.2. Mutations in APP have also been found in families segregating hemorrhagic stroke due to congophilic βA4 amyloid angiopathy (CAA) both in the presence and absence of AD. These mutations are located close to known proteolytic cleavage sites in APP, either at the N-terminal or C-terminal site or within the sequence of βA4 amyloid, the proteolytic product found in AD and CAA brain lesions. cDNA transfection experiments have indicated that these APP mutations interfere with the normal processing of APP, causing either an overproduction of βA4 amyloid or a longer βA4 amyloid that is more prone to aggregation. We have initiated cDNA transfection experiments in COS-1 cells and have studied the production of βA4 amyloid. Our results confirm previous observations in other cell types, i.e., overproduction of βA4 amyloid is not a consistent finding in all known APP mutations.

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 84.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight 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.

References

  • Busciglio J, Gabuzda D, Matsudeira P, Yanker B (1993) Generatin of β-amyloid in the secretory pathway in neuronal and nonneuronal cells. Proc Natl Acad Sci USA 90: 2092–2096

    Article  PubMed  CAS  Google Scholar 

  • Cai X-D, Golde TE, Younkin SG (1993) Release of excess amyloid β protein from a mutant amyloid β protein precursor. Science 259: 514–516

    Article  PubMed  CAS  Google Scholar 

  • Chartier-Harlin M-C, Crawford F, Houlden H, Warren A, Hughes D, Fidani L, Goate A, Rossor M, Roques P, Hardy J, Mullan M (1991) Early-onset Alzheimer’s disease caused by mutations at codon 717 of the β-amyloid precursor protein gene. Nature 353: 844–846

    Article  PubMed  CAS  Google Scholar 

  • Chartier-Harlin M-C, Parfitt M, Legrain S, Pérez-Tur J, Brousseau T, Evans A, Berr C, Vidal O, Roques P, Gourlet V, Fruchart J-C, Delacourte A, Rossor M, Amouyel P (1994) Apolipoprotein E, e4 allele as a major risk factor for sporadic early and late-onset forms of Alzheimer’s disease: analysis of the 19q13.2 chromosomal region. Human Mol Genet 3: 569–574

    Article  CAS  Google Scholar 

  • Cheung TT, Ghiso J, Shoji M, Cai X-D, Golde T, Gandy S, Frangione B, Younkin S (1994) Characterization by radiosequencing of the carboxyl-terminal derivatives produced from normal and mutant amyloid β protein precursors amyloid. Int J Exp Clin Invest 1: 30–38

    CAS  Google Scholar 

  • Citron M, Oltersdorf T, Haass C, McConlogue L, Hing AY, Seubert P, Vigo-Pelfrey C, Lieberburg I, Selkoe DJ (1992) Mutation of the β-amyloid precursor protein in familial Alzheimer’s disease increases fi-protein production. Nature 360: 672–674

    Article  PubMed  CAS  Google Scholar 

  • Clements A, Walsh DM, Williams CH, Allsop D (1993) Effects of the mutations G1u22 to Gln and Ala21 to Gly on the aggregation of a synthetic fragment of the Alzheimer’s amyloid β/A4 peptide. Neurosci Lett 161: 17–20

    Article  PubMed  CAS  Google Scholar 

  • Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993) Gene dose of Apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261: 921–923

    CAS  Google Scholar 

  • Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PC, Rimmler JB, Locke PA, Conneally PM, Schmader KE, Small GW, Roses AD, Haines JL, PericakVance MA (1994) Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nature Genet 7: 180–184

    CAS  Google Scholar 

  • Deng WP, Nickoloff JA (1992) Site directed mutagenesis of virtually any plasmid by eliminating a unique side. Anal Biochem 200: 81–88

    Article  PubMed  CAS  Google Scholar 

  • Dovey HF, Suomensaari-Chrysler S, Lieberburg I, Sinha S, Keim PS (1993) Cells with a familial Alzheimer’s disease mutation produce authentic β-peptide. Neurochemistry 4: 1039–1042

    CAS  Google Scholar 

  • Esch FS, Keim PS, Beattie EC, Blacher RW, Culwell AR, Oltersdorf T, McClure D, Ward PJ (1990) Cleavage of amyloid β peptide during constitutive processing of its precursor. Science 248: 1122–1124

    Article  PubMed  CAS  Google Scholar 

  • Estus S, Golde TE, Kunishita T, Blades D, Lowery D, Eisen M, Udiak M, Qu X, Tabira T, Greenberg BD, Younkin SG (1992) Potentially amyloidogenic, carboxyl-terminal derivatives of the amyloid protein precursor. Science 255: 726–728

    Article  PubMed  CAS  Google Scholar 

  • Felsenstein KM, Lewis-Higgins L (1993) Processing of the β-amyloid precursor protein carrying the familial, Dutch-type, and a novel recombinant C-terminal mutation. Neurosci Lett 152: 185–189

    Article  PubMed  CAS  Google Scholar 

  • Felsenstein KM, Hunihan LW, Roberts SB (1994) Altered cleavage and secretion of a recombinant β-APP bearing the Swedish familial Alzheimer’s disease mutation. Nature Genet 6: 251–256

    Article  PubMed  CAS  Google Scholar 

  • Fraser PE, Nguyen JT, Inouye H, Surewicz WK, Selkoe DJ, Podlisny MB, Kirschner DA (1992) Fibril formation by primate, rodent and Dutch-hemorrhagic analogues of Alzheimer amyloid fi-protein. Biochem 31: 10716–10723

    Article  CAS  Google Scholar 

  • Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L, Mant R, Newton P, Rooke K, Roques P, Talbot C, Pericak-Vance M, Roses A, Williamson R, Rossor M, Owen M, Hardy J (1991) Segregation of a missence mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349: 704–706

    Article  PubMed  CAS  Google Scholar 

  • Golde T, Estus S, Younkin LH, Selkoe DJ, Younkin SG (1992) Processing of the amyloid protein precursor to potentially amyloidogenic derivatives. Science 255: 728–730

    Article  PubMed  CAS  Google Scholar 

  • Haan J, Hardy JA, Roos RA (1991) Hereditary cerebral hemorrhage with amyloidosis-Dutch type: its importance for Alzheimer research. Trends Neurosci 14: 231–234

    Article  PubMed  CAS  Google Scholar 

  • Haan J, van Broeckhoven C, van Duijn CM, Voorhoeve E, van Harscamp F, van Swieten JC, Maat-Schieman MLC, Roos RAC, Bakker E (1994) The apolipoprotein E r4 allele does not influence the clinical expression of the amyloid precursor protein-gene codon 693 or 692 mutations. Ann Neurol 36: 434–437

    CAS  Google Scholar 

  • Haass C, Selkoe DJ (1993) Cellular processing of β-amyloid precursor protein and the genesis of amyloid β-peptide. Cell 75: 1039–1042

    Article  PubMed  CAS  Google Scholar 

  • Haass C, Koo EH, Mellon A, Hung AY, Selkoe DJ (1992a) Targeting of cell-surface β-amyloid precursor protein to lysosomes: alternative processing into amyloid-bearing fragments. Nature 357: 500–503

    Article  PubMed  CAS  Google Scholar 

  • Haass C, Schlossmacher MG, Hung AY, Vigo-Pelfrey C, Mellon A, Ostaszewski BL, Lieberburg I, Koo EH, Schenk D, Teplow DB, Selkoe DJ (1992b) Amyloid β-peptide is produced by cultured cells during normal metabolism. Nature 359: 322–327

    Article  PubMed  CAS  Google Scholar 

  • Haass C, Hung AY, Selkoe DJ, Teplow DB (1994) Mutations assosiated with a locus for familial Alzheimer’s disease result in alternative processing of amyloid β-protein precursor. J Biol Chem 269: 17741–17748

    PubMed  CAS  Google Scholar 

  • Hardy J, Houlden H, Collinge J, Kennedy A, Newman S, Rossor M, Lannfelt L, Lilius L, Winblad B, Crook R, Duff K (1993) Apolipoprotein E genotype and Alzheimer’s disease. Lancet 342: 737–738

    Google Scholar 

  • Hendriks L, van Duijn C, Cras P, Cruts M, Van Hul W, van Harskamp F, Warren A, McInnis M, Antonarakis SE, Martin JJ, Hofman A, Van Broeckhoven C (1992) Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the β-amyloid precursor protein gene. Nature Genet 1: 218–221

    Article  PubMed  CAS  Google Scholar 

  • Jarrett JT, Berger EP, Lansbury PT Jr (1993) The carboxy terminus of the β amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer’s disease. Biochemistry 32: 4693–4697

    Article  PubMed  CAS  Google Scholar 

  • Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, Multhaup F, 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 

  • Kitaguchi N, Takahashi Y, Tokushima Y, Shiojiri S, Ito H (1988) Novel precursor of Alzheimer’s disease amyloid protein shows protease inhibitory activity. Nature 331: 530–532

    Article  PubMed  CAS  Google Scholar 

  • Levy E, Carman M, Fernandez-Madrid IJ, Power M, Lieberburg I, van Duinen S, Bots G, Luyendijk W, Frangione B (1990) Mutation of the Alzheimer’s disease amyloid gene in hereditary cerebral haemorrhage, Dutch type. Science 248: 1124–1126

    Article  Google Scholar 

  • Luthman H, Magnussson G (1983) High efficiency polyoma DNA transfection of chloroquine treated cells. Nucl Acids Res 11: 1295–1308

    Article  PubMed  CAS  Google Scholar 

  • Maruyama K, Usami M, Yamao-Harigaya W, Tagawa K, Ishiura S (1991) Mutation of Glu693 to Gln or Va1717 to Ile has no effect on the processing of Alzheimer amyloid precursor protein expressed in COS-1 cells by cDNA transfection. Neurosci Lett 132: 97–100

    Article  PubMed  CAS  Google Scholar 

  • Mullan M, Crawford F, Axelman K, Houlden H, Lilius L, Winblad B, Lannfelt L (1992) A pathogenic mutation for probable Alzheimer’s disease in the APP gene at the N-terminus of β-amyloid. Nature Genet 1: 345–347

    Article  PubMed  CAS  Google Scholar 

  • Murrell J, Farlow M, Ghetti B, Benson M (1991) A mutation in the amyloid precursor protein associated with hereditary Alzheimer’s disease. Science 254: 97–99

    Article  PubMed  CAS  Google Scholar 

  • Ponte P, DeWhitt PG, Schilling J, Miller J, Hsu D, Greenberg B, Davis K, Wallace W, Lieberburg I, Fuller F, Cordell B (1988) A new A4 amyloid mRNA contains a domain homologous to serine proteinase inhibitors. Nature 331: 525–527

    Article  PubMed  CAS  Google Scholar 

  • Saunders AM, Strittmatter WJ, Schmechel D, St. George-Hysolp PH, Pericak-Vance MA, Joo SH, Rosi BL, Gusella JF, Crapper-McLachlan DR, Alberts MJ, Hulette C, Crain B, Goldgaber D, Roses AD (1993) Association of apolipoprotein E allele E4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 43: 1467–1472

    CAS  Google Scholar 

  • Seubert P, Vigo-Pelfrey C, Esch F, Lee M, Dovey H, Davis D, Sinha S, Schlossmacher M, Whaley J, Swindlehurst C, McCormack R, Wolfert R, Selkoe D, Lieberburg I, Schenk D (1992) Isolation and quantification of soluble Alzheimer’s β-peptide from biological fluids. Nature 359: 325–327

    Article  PubMed  CAS  Google Scholar 

  • Seubert P, Oltersdorf T, Lee MG, Barbur R, Blomquist C, Davis DL, Bryant K, Fritz LC, Galasko D, Thal LJ, Lieberburg I, Schenk DB (1993) Secretion of β-amyloid precursor protein cleaved at the amino terminus of the β-amyloid peptide. Nature 361: 260–263

    Article  PubMed  CAS  Google Scholar 

  • Shoji M, Golde TE, Ghiso J, Cheung TT, Estus S, Shaffer LM, Cai X-D, McKay DM, Tintner R, Frangione B, Younkin SG (1992) Production of the Alzheimer’s amyloid β protein by normal proteolytic processing. Science 258: 126–129

    Article  PubMed  CAS  Google Scholar 

  • Schmechel DE, Saunders AM, Strittmatter WJ, Crain B, Hulette C, Joo SH, Pericak-Vance MA, Goldgaber D, Roses AD (1993) Increased amyloid fi-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc Natl Acad Sci USA 90: 9646–9653

    Google Scholar 

  • Strittmatter WJ, Weisgraber KH, Huang D, Dong L, Salvesen GS, Pericak-Vance M, Schmechel D, Saunders AM, Goldgaber D, Roses AD (1993a) Binding of human apolipoprotein E to synthetic amyloid β peptide: isoform-specific effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci USA 90: 8098–8102

    CAS  Google Scholar 

  • Strittmatter WJ, Saunders AL, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD (1993b) Apolipoprotein E: high avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 90: 1977–1981

    Article  PubMed  CAS  Google Scholar 

  • Suzuki N, Cheung TT, Cai X-D, Odaka A, Otvos Jr L, Eckman C, Golde TE, Younkin SG (1994) An increased percentage of long amyloid β protein secreted by famililal amyloid β protein precuresor (βAPP717) mutants. Science 264: 1336–1340

    Article  PubMed  CAS  Google Scholar 

  • Tanzi RE, Gusella JF, Watkins PC, Bruns GAP, St George-Hyslop P, Van Keuren ML, Patterson D, Pagan S, Kurnit DM, Neve RL (1987) Amyloid 13 protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science 235: 880–884

    Article  PubMed  CAS  Google Scholar 

  • Tanzi RE, McClatchey AI, Lamperti ED, Villa-Komaroff L, Gusella JF, Neve RL (1988) Protease inhibitor domain encoded by an amyloid protein precursor mRNA associated with Alzheimer’s disease. Nature 331: 528–530

    Article  PubMed  CAS  Google Scholar 

  • van Duijn C, de Knijf P, Cruts M, Wehnert A, Havekes LM, Hofman A, Van Broeckhoven C (1994) Apolipoprotein E4 allele in a population-based study of early-onset Alzheimer’s disease. Nature Genet 7: 74–78

    Article  PubMed  Google Scholar 

  • Van Broeckhoven CL (1994) Molecular genetics of Alzheimer disease: identification of genes and gene mutations. Eur Neurol (in press)

    Google Scholar 

  • Wisniewski T, Ghiso J, Frangione B (1991) Peptides homologous to the amyloid protein of Alzheimer’s disease containing a glutamine for glutamic acid substitution have accelerated amyloid fibril formation. Biochem Biophys Res Commun 179: 1247–1254

    Article  PubMed  CAS  Google Scholar 

  • Wisniewski T, Frangione B (1992) Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid. Neurosci Lett 135: 235–238

    Article  PubMed  CAS  Google Scholar 

  • Yoshikai S-I, Sakaki H, Dohura K, Furuya H, Sakaki Y (1990) Genomic organization of the human amyloid beta-protein precursor gene. Gene 87: 257–263

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Neurogenetics, Born Bunge Foundation, Department of Biochemistry, University of Antwerp (UTA), Universiteitsplein 1, 2610, Antwerp, Belgium

    L. Hendriks

Authors
  1. L. Hendriks
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P. Cras
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J.-J. Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C. Van Broeckhoven
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Harvard Medical School, Brigham and Women’s Hospital, 221 Longwood Avenue, 02115, Boston, MA, USA

    K. S. Kosik M.D. (Associate Professor of Neurology and Neuroscience) & D. J. Selkoe M.D. (Professor of Neurology and Neuroscience) (Associate Professor of Neurology and Neuroscience) &  (Professor of Neurology and Neuroscience)

  2. Fondation IPSEN, 24, rue Erlanger, 75781, Paris, France

    Y. Christen Ph.D.

Rights and permissions

Reprints and permissions

Copyright information

© 1995 Springer-Verlag Berlin Heidelberg

About this paper

Cite this paper

Hendriks, L., Cras, P., Martin, JJ., Van Broeckhoven, C. (1995). Alzheimer’s Disease and Hemorrhagic Stroke: Their Relationship to βA4 Amyloid Deposition. In: Kosik, K.S., Selkoe, D.J., Christen, Y. (eds) Alzheimer’s Disease: Lessons from Cell Biology. Research and Perspectives in Alzheimer’s Disease. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-79423-0_4

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-79423-0_4

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-79425-4

  • Online ISBN: 978-3-642-79423-0

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation