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. 1990 Feb;87(4):1561–1565. doi: 10.1073/pnas.87.4.1561

Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport.

E H Koo 1, S S Sisodia 1, D R Archer 1, L J Martin 1, A Weidemann 1, K Beyreuther 1, P Fischer 1, C L Masters 1, D L Price 1
PMCID: PMC53515  PMID: 1689489

Abstract

In the brains of aged humans and cases of Alzheimer disease, deposits of amyloid in senile plaques are located in proximity to nerve processes. The principal component of this extracellular amyloid is beta/A4, a peptide derived from a larger amyloid precursor protein (APP), which is actively expressed in brain and systemic organs. Mechanisms that result in the proteolysis of APP to form beta/A4, previously termed beta-amyloid protein, and the subsequent deposition of the peptide in brain are unknown. If beta/A4 in senile plaques is derived from neuronally synthesized APP and deposited at locations remote from sites of synthesis, then APP must be transported from neuronal cell bodies to distal nerve processes in proximity to deposits of amyloid. In this study, using several immunodetection methods, we demonstrate that APP is transported axonally in neurons of the rat peripheral nervous system. Moreover, our investigations show that APP is transported by means of the fast anterograde component. These findings are consistent with the hypothesis of a neuronal origin of beta/A4, in which amyloid is deposited in the brain parenchyma of aged individuals and cases of Alzheimer disease. In this setting, we suggest that APP is synthesized in neurons and delivered to dystrophic nerve endings, where subsequent alterations of local processing of APP result in deposits of brain amyloid.

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Selected References

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

  1. Bahmanyar S., Higgins G. A., Goldgaber D., Lewis D. A., Morrison J. H., Wilson M. C., Shankar S. K., Gajdusek D. C. Localization of amyloid beta protein messenger RNA in brains from patients with Alzheimer's disease. Science. 1987 Jul 3;237(4810):77–80. doi: 10.1126/science.3299701. [DOI] [PubMed] [Google Scholar]
  2. Castaño E. M., Ghiso J., Prelli F., Gorevic P. D., Migheli A., Frangione B. In vitro formation of amyloid fibrils from two synthetic peptides of different lengths homologous to Alzheimer's disease beta-protein. Biochem Biophys Res Commun. 1986 Dec 15;141(2):782–789. doi: 10.1016/s0006-291x(86)80241-8. [DOI] [PubMed] [Google Scholar]
  3. Cohen M. L., Golde T. E., Usiak M. F., Younkin L. H., Younkin S. G. In situ hybridization of nucleus basalis neurons shows increased beta-amyloid mRNA in Alzheimer disease. Proc Natl Acad Sci U S A. 1988 Feb;85(4):1227–1231. doi: 10.1073/pnas.85.4.1227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Couraud J. Y., Di Giamberardino L. Axonal transport of the molecular forms of acetylcholinesterase in chick sciatic nerve. J Neurochem. 1980 Nov;35(5):1053–1066. doi: 10.1111/j.1471-4159.1980.tb07859.x. [DOI] [PubMed] [Google Scholar]
  5. Dyrks T., Weidemann A., Multhaup G., Salbaum J. M., Lemaire H. G., Kang J., Müller-Hill B., Masters C. L., Beyreuther K. Identification, transmembrane orientation and biogenesis of the amyloid A4 precursor of Alzheimer's disease. EMBO J. 1988 Apr;7(4):949–957. doi: 10.1002/j.1460-2075.1988.tb02900.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Fonnum F. Radiochemical micro assays for the determination of choline acetyltransferase and acetylcholinesterase activities. Biochem J. 1969 Nov;115(3):465–472. doi: 10.1042/bj1150465. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Glenner G. G., Wong C. W. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun. 1984 May 16;120(3):885–890. doi: 10.1016/s0006-291x(84)80190-4. [DOI] [PubMed] [Google Scholar]
  8. Goedert M. Neuronal localization of amyloid beta protein precursor mRNA in normal human brain and in Alzheimer's disease. EMBO J. 1987 Dec 1;6(12):3627–3632. doi: 10.1002/j.1460-2075.1987.tb02694.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Grafstein B., Forman D. S. Intracellular transport in neurons. Physiol Rev. 1980 Oct;60(4):1167–1283. doi: 10.1152/physrev.1980.60.4.1167. [DOI] [PubMed] [Google Scholar]
  10. Higgins G. A., Lewis D. A., Bahmanyar S., Goldgaber D., Gajdusek D. C., Young W. G., Morrison J. H., Wilson M. C. Differential regulation of amyloid-beta-protein mRNA expression within hippocampal neuronal subpopulations in Alzheimer disease. Proc Natl Acad Sci U S A. 1988 Feb;85(4):1297–1301. doi: 10.1073/pnas.85.4.1297. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Johnson S. A., Pasinetti G. M., May P. C., Ponte P. A., Cordell B., Finch C. E. Selective reduction of mRNA for the beta-amyloid precursor protein that lacks a Kunitz-type protease inhibitor motif in cortex from Alzheimer brains. Exp Neurol. 1988 Nov;102(2):264–268. doi: 10.1016/0014-4886(88)90104-5. [DOI] [PubMed] [Google Scholar]
  12. 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]
  13. 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]
  14. 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]
  15. Kitt C. A., Price D. L., Struble R. G., Cork L. C., Wainer B. H., Becher M. W., Mobley W. C. Evidence for cholinergic neurites in senile plaques. Science. 1984 Dec 21;226(4681):1443–1445. doi: 10.1126/science.6505701. [DOI] [PubMed] [Google Scholar]
  16. Lewis D. A., Higgins G. A., Young W. G., Goldgaber D., Gajdusek D. C., Wilson M. C., Morrison J. H. Distribution of precursor amyloid-beta-protein messenger RNA in human cerebral cortex: relationship to neurofibrillary tangles and neuritic plaques. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1691–1695. doi: 10.1073/pnas.85.5.1691. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Masters C. L., Multhaup G., Simms G., Pottgiesser J., Martins R. N., Beyreuther K. Neuronal origin of a cerebral amyloid: neurofibrillary tangles of Alzheimer's disease contain the same protein as the amyloid of plaque cores and blood vessels. EMBO J. 1985 Nov;4(11):2757–2763. doi: 10.1002/j.1460-2075.1985.tb04000.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Masters C. L., Simms G., Weinman N. A., Multhaup G., McDonald B. L., Beyreuther K. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A. 1985 Jun;82(12):4245–4249. doi: 10.1073/pnas.82.12.4245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Müller-Hill B., Beyreuther K. Molecular biology of Alzheimer's disease. Annu Rev Biochem. 1989;58:287–307. doi: 10.1146/annurev.bi.58.070189.001443. [DOI] [PubMed] [Google Scholar]
  20. Neve R. L., Finch E. A., Dawes L. R. Expression of the Alzheimer amyloid precursor gene transcripts in the human brain. Neuron. 1988 Oct;1(8):669–677. doi: 10.1016/0896-6273(88)90166-3. [DOI] [PubMed] [Google Scholar]
  21. Palmert M. R., Golde T. E., Cohen M. L., Kovacs D. M., Tanzi R. E., Gusella J. F., Usiak M. F., Younkin L. H., Younkin S. G. Amyloid protein precursor messenger RNAs: differential expression in Alzheimer's disease. Science. 1988 Aug 26;241(4869):1080–1084. doi: 10.1126/science.2457949. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. 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]
  24. Powers R. E., Struble R. G., Casanova M. F., O'Connor D. T., Kitt C. A., Price D. L. Innervation of human hippocampus by noradrenergic systems: normal anatomy and structural abnormalities in aging and in Alzheimer's disease. Neuroscience. 1988 May;25(2):401–417. doi: 10.1016/0306-4522(88)90248-5. [DOI] [PubMed] [Google Scholar]
  25. Price D. L., Koo E. H., Unterbeck A. Cellular and molecular biology of Alzheimer's disease. Bioessays. 1989 Feb-Mar;10(2-3):69–74. doi: 10.1002/bies.950100208. [DOI] [PubMed] [Google Scholar]
  26. Price D. L. New perspectives on Alzheimer's disease. Annu Rev Neurosci. 1986;9:489–512. doi: 10.1146/annurev.ne.09.030186.002421. [DOI] [PubMed] [Google Scholar]
  27. Schubert D., LaCorbiere M., Saitoh T., Cole G. Characterization of an amyloid beta precursor protein that binds heparin and contains tyrosine sulfate. Proc Natl Acad Sci U S A. 1989 Mar;86(6):2066–2069. doi: 10.1073/pnas.86.6.2066. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Selkoe D. J. Biochemistry of altered brain proteins in Alzheimer's disease. Annu Rev Neurosci. 1989;12:463–490. doi: 10.1146/annurev.ne.12.030189.002335. [DOI] [PubMed] [Google Scholar]
  29. 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]
  30. 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]
  31. 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]
  32. Wiedenmann B., Franke W. W. Identification and localization of synaptophysin, an integral membrane glycoprotein of Mr 38,000 characteristic of presynaptic vesicles. Cell. 1985 Jul;41(3):1017–1028. doi: 10.1016/s0092-8674(85)80082-9. [DOI] [PubMed] [Google Scholar]

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