Skip to main content
PMC home page
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1991 Jun;138(6):1423–1435.

Homology of the amyloid beta protein precursor in monkey and human supports a primate model for beta amyloidosis in Alzheimer's disease.

M B Podlisny 1, D R Tolan 1, D J Selkoe 1
PMCID: PMC1886384  PMID: 1905108

Abstract

Progressive cerebral deposition of the amyloid beta-protein (A beta P) occurs in Alzheimer's disease and during aging of certain mammals (eg, human, monkey, dog) but not others (eg, mouse, rat). The authors cloned and sequenced a full-length cDNA encoding the beta-protein precursor (beta APP) of cynomolgus monkey. The predicted amino acid sequence of the 695-residue protein is completely homologous to that of human. The alternatively transcribed exons encoding the Kunitz protease inhibitor region in monkey were cloned, showing only a single conservative amino acid substitution in the 751-residue form of beta APP and four substitutions in beta APP770. Immunoblots of cerebral cortex with antibodies to various beta APP domains showed highly similar beta APP polypeptides in human and monkey, in contrast to those of mouse and rat. The latter differences reflect sequence substitutions, transcriptional regulation, and possibly post-translational modifications that may decrease the amyloidogenic potential of rodent beta APP. Immunocytochemistry of aged cynomolgus brain showed A beta P deposited in blood vessels and diffuse and compacted plaques closely resembling those of humans, and the presence of beta-amyloid-associated proteins (alpha 1-antichymotrypsin; complements C1q and C3c) characteristic of A beta P deposits in Alzheimer's disease. The authors' findings demonstrate that cynomolgus monkey and perhaps other primates provide a close animal model for examining the early transcriptional and post-translational processing of beta APP that precedes A beta P deposition during aging and in Alzheimer's disease.

Full text

PDF
1432

Images in this article

1429Figure 4
on p.1429
1430Figure 5
on p.1430
1431Figure 6
on p.1431

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abraham C. R., Selkoe D. J., Potter H. Immunochemical identification of the serine protease inhibitor alpha 1-antichymotrypsin in the brain amyloid deposits of Alzheimer's disease. Cell. 1988 Feb 26;52(4):487–501. doi: 10.1016/0092-8674(88)90462-x. [DOI] [PubMed] [Google Scholar]
  2. Abraham C. R., Selkoe D. J., Potter H., Price D. L., Cork L. C. Alpha 1-antichymotrypsin is present together with the beta-protein in monkey brain amyloid deposits. Neuroscience. 1989;32(3):715–720. doi: 10.1016/0306-4522(89)90292-3. [DOI] [PubMed] [Google Scholar]
  3. Abraham C. R., Shirahama T., Potter H. Alpha 1-antichymotrypsin is associated solely with amyloid deposits containing the beta-protein. Amyloid and cell localization of alpha 1-antichymotrypsin. Neurobiol Aging. 1990 Mar-Apr;11(2):123–129. doi: 10.1016/0197-4580(90)90045-2. [DOI] [PubMed] [Google Scholar]
  4. Anderson J. P., Refolo L. M., Wallace W., Mehta P., Krishnamurthi M., Gotlib J., Bierer L., Haroutunian V., Perl D., Robakis N. K. Differential brain expression of the Alzheimer's amyloid precursor protein. EMBO J. 1989 Dec 1;8(12):3627–3632. doi: 10.1002/j.1460-2075.1989.tb08536.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Anderton B. H., Breinburg D., Downes M. J., Green P. J., Tomlinson B. E., Ulrich J., Wood J. N., Kahn J. Monoclonal antibodies show that neurofibrillary tangles and neurofilaments share antigenic determinants. Nature. 1982 Jul 1;298(5869):84–86. doi: 10.1038/298084a0. [DOI] [PubMed] [Google Scholar]
  6. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1006/abio.1976.9999. [DOI] [PubMed] [Google Scholar]
  7. Dahl D., Bignami A. Glial fibrillary acidic protein from normal human brain. Purification and properties. Brain Res. 1973 Jul 27;57(2):343–360. doi: 10.1016/0006-8993(73)90141-8. [DOI] [PubMed] [Google Scholar]
  8. Devereux J., Haeberli P., Smithies O. A comprehensive set of sequence analysis programs for the VAX. Nucleic Acids Res. 1984 Jan 11;12(1 Pt 1):387–395. doi: 10.1093/nar/12.1part1.387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Eikelenboom P., Stam F. C. Immunoglobulins and complement factors in senile plaques. An immunoperoxidase study. Acta Neuropathol. 1982;57(2-3):239–242. doi: 10.1007/BF00685397. [DOI] [PubMed] [Google Scholar]
  10. Esch F. S., Keim P. S., Beattie E. C., Blacher R. W., Culwell A. R., Oltersdorf T., McClure D., Ward P. J. Cleavage of amyloid beta peptide during constitutive processing of its precursor. Science. 1990 Jun 1;248(4959):1122–1124. doi: 10.1126/science.2111583. [DOI] [PubMed] [Google Scholar]
  11. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  12. Gandy S., Czernik A. J., Greengard P. Phosphorylation of Alzheimer disease amyloid precursor peptide by protein kinase C and Ca2+/calmodulin-dependent protein kinase II. Proc Natl Acad Sci U S A. 1988 Aug;85(16):6218–6221. doi: 10.1073/pnas.85.16.6218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gergen J. P., Stern R. H., Wensink P. C. Filter replicas and permanent collections of recombinant DNA plasmids. Nucleic Acids Res. 1979 Dec 20;7(8):2115–2136. doi: 10.1093/nar/7.8.2115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Giaccone G., Tagliavini F., Linoli G., Bouras C., Frigerio L., Frangione B., Bugiani O. Down patients: extracellular preamyloid deposits precede neuritic degeneration and senile plaques. Neurosci Lett. 1989 Feb 13;97(1-2):232–238. doi: 10.1016/0304-3940(89)90169-9. [DOI] [PubMed] [Google Scholar]
  15. Golde T. E., Estus S., Usiak M., Younkin L. H., Younkin S. G. Expression of beta amyloid protein precursor mRNAs: recognition of a novel alternatively spliced form and quantitation in Alzheimer's disease using PCR. Neuron. 1990 Feb;4(2):253–267. doi: 10.1016/0896-6273(90)90100-t. [DOI] [PubMed] [Google Scholar]
  16. Goldgaber D., Lerman M. I., McBride O. W., Saffiotti U., Gajdusek D. C. Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer's disease. Science. 1987 Feb 20;235(4791):877–880. doi: 10.1126/science.3810169. [DOI] [PubMed] [Google Scholar]
  17. Hanahan D., Meselson M. Plasmid screening at high colony density. Methods Enzymol. 1983;100:333–342. doi: 10.1016/0076-6879(83)00066-x. [DOI] [PubMed] [Google Scholar]
  18. Itagaki S., McGeer P. L., Akiyama H., Zhu S., Selkoe D. Relationship of microglia and astrocytes to amyloid deposits of Alzheimer disease. J Neuroimmunol. 1989 Oct;24(3):173–182. doi: 10.1016/0165-5728(89)90115-x. [DOI] [PubMed] [Google Scholar]
  19. Joachim C. L., Duffy L. K., Morris J. H., Selkoe D. J. Protein chemical and immunocytochemical studies of meningovascular beta-amyloid protein in Alzheimer's disease and normal aging. Brain Res. 1988 Nov 22;474(1):100–111. doi: 10.1016/0006-8993(88)90673-7. [DOI] [PubMed] [Google Scholar]
  20. Joachim C. L., Mori H., Selkoe D. J. Amyloid beta-protein deposition in tissues other than brain in Alzheimer's disease. Nature. 1989 Sep 21;341(6239):226–230. doi: 10.1038/341226a0. [DOI] [PubMed] [Google Scholar]
  21. Kang J., Lemaire H. G., Unterbeck A., Salbaum J. M., Masters C. L., Grzeschik K. H., Multhaup G., Beyreuther K., Müller-Hill B. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature. 1987 Feb 19;325(6106):733–736. doi: 10.1038/325733a0. [DOI] [PubMed] [Google Scholar]
  22. Kang J., Müller-Hill B. The sequence of the two extra exons in rat preA4. Nucleic Acids Res. 1989 Mar 11;17(5):2130–2130. doi: 10.1093/nar/17.5.2130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kirschner D. A., Inouye H., Duffy L. K., Sinclair A., Lind M., Selkoe D. J. Synthetic peptide homologous to beta protein from Alzheimer disease forms amyloid-like fibrils in vitro. Proc Natl Acad Sci U S A. 1987 Oct;84(19):6953–6957. doi: 10.1073/pnas.84.19.6953. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kitaguchi N., Takahashi Y., Tokushima Y., Shiojiri S., Ito H. Novel precursor of Alzheimer's disease amyloid protein shows protease inhibitory activity. Nature. 1988 Feb 11;331(6156):530–532. doi: 10.1038/331530a0. [DOI] [PubMed] [Google Scholar]
  25. Koo E. H., Sisodia S. S., Cork L. C., Unterbeck A., Bayney R. M., Price D. L. Differential expression of amyloid precursor protein mRNAs in cases of Alzheimer's disease and in aged nonhuman primates. Neuron. 1990 Jan;4(1):97–104. doi: 10.1016/0896-6273(90)90446-m. [DOI] [PubMed] [Google Scholar]
  26. Kosik K. S., Joachim C. L., Selkoe D. J. Microtubule-associated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer disease. Proc Natl Acad Sci U S A. 1986 Jun;83(11):4044–4048. doi: 10.1073/pnas.83.11.4044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  28. Motte J., Williams R. S. Age-related changes in the density and morphology of plaques and neurofibrillary tangles in Down syndrome brain. Acta Neuropathol. 1989;77(5):535–546. doi: 10.1007/BF00687256. [DOI] [PubMed] [Google Scholar]
  29. Oltersdorf T., Fritz L. C., Schenk D. B., Lieberburg I., Johnson-Wood K. L., Beattie E. C., Ward P. J., Blacher R. W., Dovey H. F., Sinha S. The secreted form of the Alzheimer's amyloid precursor protein with the Kunitz domain is protease nexin-II. Nature. 1989 Sep 14;341(6238):144–147. doi: 10.1038/341144a0. [DOI] [PubMed] [Google Scholar]
  30. Oltersdorf T., Ward P. J., Henriksson T., Beattie E. C., Neve R., Lieberburg I., Fritz L. C. The Alzheimer amyloid precursor protein. Identification of a stable intermediate in the biosynthetic/degradative pathway. J Biol Chem. 1990 Mar 15;265(8):4492–4497. [PubMed] [Google Scholar]
  31. Palmert M. R., Podlisny M. B., Witker D. S., Oltersdorf T., Younkin L. H., Selkoe D. J., Younkin S. G. Antisera to an amino-terminal peptide detect the amyloid protein precursor of Alzheimer's disease and recognize senile plaques. Biochem Biophys Res Commun. 1988 Oct 14;156(1):432–437. doi: 10.1016/s0006-291x(88)80859-3. [DOI] [PubMed] [Google Scholar]
  32. Palmert M. R., Podlisny M. B., Witker D. S., Oltersdorf T., Younkin L. H., Selkoe D. J., Younkin S. G. The beta-amyloid protein precursor of Alzheimer disease has soluble derivatives found in human brain and cerebrospinal fluid. Proc Natl Acad Sci U S A. 1989 Aug;86(16):6338–6342. doi: 10.1073/pnas.86.16.6338. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Palmert M. R., Siedlak S. L., Podlisny M. B., Greenberg B., Shelton E. R., Chan H. W., Usiak M., Selkoe D. J., Perry G., Younkin S. G. Soluble derivatives of the beta amyloid protein precursor of Alzheimer's disease are labeled by antisera to the beta amyloid protein. Biochem Biophys Res Commun. 1989 Nov 30;165(1):182–188. doi: 10.1016/0006-291x(89)91052-8. [DOI] [PubMed] [Google Scholar]
  34. Podlisny M. B., Lee G., Selkoe D. J. Gene dosage of the amyloid beta precursor protein in Alzheimer's disease. Science. 1987 Oct 30;238(4827):669–671. doi: 10.1126/science.2960019. [DOI] [PubMed] [Google Scholar]
  35. Podlisny M. B., Mammen A. L., Schlossmacher M. G., Palmert M. R., Younkin S. G., Selkoe D. J. Detection of soluble forms of the beta-amyloid precursor protein in human plasma. Biochem Biophys Res Commun. 1990 Mar 30;167(3):1094–1101. doi: 10.1016/0006-291x(90)90635-z. [DOI] [PubMed] [Google Scholar]
  36. Ponte P., Gonzalez-DeWhitt P., Schilling J., Miller J., Hsu D., Greenberg B., Davis K., Wallace W., Lieberburg I., Fuller F. A new A4 amyloid mRNA contains a domain homologous to serine proteinase inhibitors. Nature. 1988 Feb 11;331(6156):525–527. doi: 10.1038/331525a0. [DOI] [PubMed] [Google Scholar]
  37. Robakis N. K., Ramakrishna N., Wolfe G., Wisniewski H. M. Molecular cloning and characterization of a cDNA encoding the cerebrovascular and the neuritic plaque amyloid peptides. Proc Natl Acad Sci U S A. 1987 Jun;84(12):4190–4194. doi: 10.1073/pnas.84.12.4190. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Rozemuller J. M., Eikelenboom P., Stam F. C., Beyreuther K., Masters C. L. A4 protein in Alzheimer's disease: primary and secondary cellular events in extracellular amyloid deposition. J Neuropathol Exp Neurol. 1989 Nov;48(6):674–691. doi: 10.1097/00005072-198911000-00009. [DOI] [PubMed] [Google Scholar]
  39. Rumble B., Retallack R., Hilbich C., Simms G., Multhaup G., Martins R., Hockey A., Montgomery P., Beyreuther K., Masters C. L. Amyloid A4 protein and its precursor in Down's syndrome and Alzheimer's disease. N Engl J Med. 1989 Jun 1;320(22):1446–1452. doi: 10.1056/NEJM198906013202203. [DOI] [PubMed] [Google Scholar]
  40. Saiki R. K., Bugawan T. L., Horn G. T., Mullis K. B., Erlich H. A. Analysis of enzymatically amplified beta-globin and HLA-DQ alpha DNA with allele-specific oligonucleotide probes. Nature. 1986 Nov 13;324(6093):163–166. doi: 10.1038/324163a0. [DOI] [PubMed] [Google Scholar]
  41. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Selkoe D. J., Abraham C. R., Podlisny M. B., Duffy L. K. Isolation of low-molecular-weight proteins from amyloid plaque fibers in Alzheimer's disease. J Neurochem. 1986 Jun;46(6):1820–1834. doi: 10.1111/j.1471-4159.1986.tb08501.x. [DOI] [PubMed] [Google Scholar]
  43. Selkoe D. J., Bell D. S., Podlisny M. B., Price D. L., Cork L. C. Conservation of brain amyloid proteins in aged mammals and humans with Alzheimer's disease. Science. 1987 Feb 20;235(4791):873–877. doi: 10.1126/science.3544219. [DOI] [PubMed] [Google Scholar]
  44. Selkoe D. J., Podlisny M. B., Joachim C. L., Vickers E. A., Lee G., Fritz L. C., Oltersdorf T. Beta-amyloid precursor protein of Alzheimer disease occurs as 110- to 135-kilodalton membrane-associated proteins in neural and nonneural tissues. Proc Natl Acad Sci U S A. 1988 Oct;85(19):7341–7345. doi: 10.1073/pnas.85.19.7341. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Shivers B. D., Hilbich C., Multhaup G., Salbaum M., Beyreuther K., Seeburg P. H. Alzheimer's disease amyloidogenic glycoprotein: expression pattern in rat brain suggests a role in cell contact. EMBO J. 1988 May;7(5):1365–1370. doi: 10.1002/j.1460-2075.1988.tb02952.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Struble R. G., Price D. L., Jr, Cork L. C., Price D. L. Senile plaques in cortex of aged normal monkeys. Brain Res. 1985 Dec 30;361(1-2):267–275. doi: 10.1016/0006-8993(85)91298-3. [DOI] [PubMed] [Google Scholar]
  47. Tagliavini F., Giaccone G., Frangione B., Bugiani O. Preamyloid deposits in the cerebral cortex of patients with Alzheimer's disease and nondemented individuals. Neurosci Lett. 1988 Nov 11;93(2-3):191–196. doi: 10.1016/0304-3940(88)90080-8. [DOI] [PubMed] [Google Scholar]
  48. Tanzi R. E., Gusella J. F., Watkins P. C., Bruns G. A., St George-Hyslop P., Van Keuren M. L., Patterson D., Pagan S., Kurnit D. M., Neve R. L. Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science. 1987 Feb 20;235(4791):880–884. doi: 10.1126/science.2949367. [DOI] [PubMed] [Google Scholar]
  49. Tanzi R. E., McClatchey A. I., Lamperti E. D., Villa-Komaroff L., Gusella J. F., Neve R. L. Protease inhibitor domain encoded by an amyloid protein precursor mRNA associated with Alzheimer's disease. Nature. 1988 Feb 11;331(6156):528–530. doi: 10.1038/331528a0. [DOI] [PubMed] [Google Scholar]
  50. Towbin H., Staehelin T., Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A. 1979 Sep;76(9):4350–4354. doi: 10.1073/pnas.76.9.4350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Verga L., Frangione B., Tagliavini F., Giaccone G., Migheli A., Bugiani O. Alzheimer patients and Down patients: cerebral preamyloid deposits differ ultrastructurally and histochemically from the amyloid of senile plaques. Neurosci Lett. 1989 Nov 6;105(3):294–299. doi: 10.1016/0304-3940(89)90636-8. [DOI] [PubMed] [Google Scholar]
  52. Weidemann A., König G., Bunke D., Fischer P., Salbaum J. M., Masters C. L., Beyreuther K. Identification, biogenesis, and localization of precursors of Alzheimer's disease A4 amyloid protein. Cell. 1989 Apr 7;57(1):115–126. doi: 10.1016/0092-8674(89)90177-3. [DOI] [PubMed] [Google Scholar]
  53. Whitson J. S., Glabe C. G., Shintani E., Abcar A., Cotman C. W. Beta-amyloid protein promotes neuritic branching in hippocampal cultures. Neurosci Lett. 1990 Mar 14;110(3):319–324. doi: 10.1016/0304-3940(90)90867-9. [DOI] [PubMed] [Google Scholar]
  54. Whitson J. S., Selkoe D. J., Cotman C. W. Amyloid beta protein enhances the survival of hippocampal neurons in vitro. Science. 1989 Mar 17;243(4897):1488–1490. doi: 10.1126/science.2928783. [DOI] [PubMed] [Google Scholar]
  55. Wiśniewski H. M., Ghetti B., Terry R. D. Neuritic (senile) plaques and filamentous changes in aged rhesus monkeys. J Neuropathol Exp Neurol. 1973 Oct;32(4):566–584. doi: 10.1097/00005072-197310000-00007. [DOI] [PubMed] [Google Scholar]
  56. Wiśniewski H., Johnson A. B., Raine C. S., Kay W. J., Terry R. D. Senile plaques and cerebral amyloidosis in aged dogs. A histochemical and ultrastructural study. Lab Invest. 1970 Sep;23(3):287–296. [PubMed] [Google Scholar]
  57. Yamada T., Sasaki H., Dohura K., Goto I., Sakaki Y. Structure and expression of the alternatively-spliced forms of mRNA for the mouse homolog of Alzheimer's disease amyloid beta protein precursor. Biochem Biophys Res Commun. 1989 Feb 15;158(3):906–912. doi: 10.1016/0006-291x(89)92808-8. [DOI] [PubMed] [Google Scholar]
  58. Yamada T., Sasaki H., Furuya H., Miyata T., Goto I., Sakaki Y. Complementary DNA for the mouse homolog of the human amyloid beta protein precursor. Biochem Biophys Res Commun. 1987 Dec 16;149(2):665–671. doi: 10.1016/0006-291x(87)90419-0. [DOI] [PubMed] [Google Scholar]
  59. Yamaguchi H., Hirai S., Morimatsu M., Shoji M., Harigaya Y. Diffuse type of senile plaques in the brains of Alzheimer-type dementia. Acta Neuropathol. 1988;77(2):113–119. doi: 10.1007/BF00687420. [DOI] [PubMed] [Google Scholar]
  60. Yankner B. A., Duffy L. K., Kirschner D. A. Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Science. 1990 Oct 12;250(4978):279–282. doi: 10.1126/science.2218531. [DOI] [PubMed] [Google Scholar]
  61. de Sauvage F., Octave J. N. A novel mRNA of the A4 amyloid precursor gene coding for a possibly secreted protein. Science. 1989 Aug 11;245(4918):651–653. doi: 10.1126/science.2569763. [DOI] [PubMed] [Google Scholar]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

RESOURCES