Skip to main content
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1996 Jun;148(6):1797–1806.

Widespread neuronal expression of the presenilin-1 early-onset Alzheimer's disease gene in the murine brain.

D H Cribbs 1, L S Chen 1, S M Bende 1, F M LaFerla 1
PMCID: PMC1861636  PMID: 8669467

Abstract

Mutations in the presenilin-1 (S182) gene have been genetically linked to early-onset Alzheimer's disease. To clarify the underlying molecular mechanism through which presenilin-1 is involved in the pathogenesis of this neurodegenerative disorder, the regional and cellular transcription profile of this gene was characterized in primary cells isolated from the murine brain by Northern blot hybridization using digoxigenin-labeled riboprobes. Our results indicate that presenilin-1 mRNA transcripts are widely distributed throughout the adult mouse brain. Furthermore, immunohistochemical labeling of hybridized sections indicates that expression was predominantly localized to neuronal cells. Neurons in the hippocampus and cerebral cortex, which are severely compromised in Alzheimer's disease, showed prominent expression of presenilin-1. In contrast, white matter areas and endothelial cells do not appear to express presenilin-1 to detectable levels. presenilin-1 transcripts, however, are also present less frequently in certain nonneuronal cell populations such as ependymal cells in the choroid plexus. Analysis of primary cells isolated from murine brain supported the results obtained by in situ hybridization and showed that cultured primary neurons and astrocytes express presenilin-1. Overall, it appears that the pattern of presenilin-1 gene expression parallels that previously described for the amyloid precursor protein.

Full text

PDF
1797

Images in this article

Selected References

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

  1. Brewer G. J., Cotman C. W. Survival and growth of hippocampal neurons in defined medium at low density: advantages of a sandwich culture technique or low oxygen. Brain Res. 1989 Aug 7;494(1):65–74. doi: 10.1016/0006-8993(89)90144-3. [DOI] [PubMed] [Google Scholar]
  2. Chartier-Harlin M. C., Crawford F., Houlden H., Warren A., Hughes D., Fidani L., Goate A., Rossor M., Roques P., Hardy J. Early-onset Alzheimer's disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. Nature. 1991 Oct 31;353(6347):844–846. doi: 10.1038/353844a0. [DOI] [PubMed] [Google Scholar]
  3. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  4. Cox K. H., DeLeon D. V., Angerer L. M., Angerer R. C. Detection of mrnas in sea urchin embryos by in situ hybridization using asymmetric RNA probes. Dev Biol. 1984 Feb;101(2):485–502. doi: 10.1016/0012-1606(84)90162-3. [DOI] [PubMed] [Google Scholar]
  5. Dewji N. N., Singer S. J. Genetic clues to Alzheimer's disease. Science. 1996 Jan 12;271(5246):159–160. doi: 10.1126/science.271.5246.159. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Goate A., Chartier-Harlin M. C., Mullan M., Brown J., Crawford F., Fidani L., Giuffra L., Haynes A., Irving N., James L. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature. 1991 Feb 21;349(6311):704–706. doi: 10.1038/349704a0. [DOI] [PubMed] [Google Scholar]
  8. Kamboh M. I., Sanghera D. K., Ferrell R. E., DeKosky S. T. APOE*4-associated Alzheimer's disease risk is modified by alpha 1-antichymotrypsin polymorphism. Nat Genet. 1995 Aug;10(4):486–488. doi: 10.1038/ng0895-486. [DOI] [PubMed] [Google Scholar]
  9. LaFerla F. M., Tinkle B. T., Bieberich C. J., Haudenschild C. C., Jay G. The Alzheimer's A beta peptide induces neurodegeneration and apoptotic cell death in transgenic mice. Nat Genet. 1995 Jan;9(1):21–30. doi: 10.1038/ng0195-21. [DOI] [PubMed] [Google Scholar]
  10. Lassmann H., Bancher C., Breitschopf H., Wegiel J., Bobinski M., Jellinger K., Wisniewski H. M. Cell death in Alzheimer's disease evaluated by DNA fragmentation in situ. Acta Neuropathol. 1995;89(1):35–41. doi: 10.1007/BF00294257. [DOI] [PubMed] [Google Scholar]
  11. Levitan D., Greenwald I. Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene. Nature. 1995 Sep 28;377(6547):351–354. doi: 10.1038/377351a0. [DOI] [PubMed] [Google Scholar]
  12. Levy-Lahad E., Wijsman E. M., Nemens E., Anderson L., Goddard K. A., Weber J. L., Bird T. D., Schellenberg G. D. A familial Alzheimer's disease locus on chromosome 1. Science. 1995 Aug 18;269(5226):970–973. doi: 10.1126/science.7638621. [DOI] [PubMed] [Google Scholar]
  13. Loo D. T., Copani A., Pike C. J., Whittemore E. R., Walencewicz A. J., Cotman C. W. Apoptosis is induced by beta-amyloid in cultured central nervous system neurons. Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):7951–7955. doi: 10.1073/pnas.90.17.7951. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. McCarthy K. D., de Vellis J. Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue. J Cell Biol. 1980 Jun;85(3):890–902. doi: 10.1083/jcb.85.3.890. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Mita S., Schon E. A., Herbert J. Widespread expression of amyloid beta-protein precursor gene in rat brain. Am J Pathol. 1989 Jun;134(6):1253–1261. [PMC free article] [PubMed] [Google Scholar]
  16. Murrell J., Farlow M., Ghetti B., Benson M. D. A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease. Science. 1991 Oct 4;254(5028):97–99. doi: 10.1126/science.1925564. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. Panoskaltsis-Mortari A., Bucy R. P. In situ hybridization with digoxigenin-labeled RNA probes: facts and artifacts. Biotechniques. 1995 Feb;18(2):300–307. [PubMed] [Google Scholar]
  19. Pike C. J., Cummings B. J., Monzavi R., Cotman C. W. Beta-amyloid-induced changes in cultured astrocytes parallel reactive astrocytosis associated with senile plaques in Alzheimer's disease. Neuroscience. 1994 Nov;63(2):517–531. doi: 10.1016/0306-4522(94)90547-9. [DOI] [PubMed] [Google Scholar]
  20. Rentrop M., Knapp B., Winter H., Schweizer J. Aminoalkylsilane-treated glass slides as support for in situ hybridization of keratin cDNAs to frozen tissue sections under varying fixation and pretreatment conditions. Histochem J. 1986 May;18(5):271–276. doi: 10.1007/BF01676237. [DOI] [PubMed] [Google Scholar]
  21. Rogaev E. I., Sherrington R., Rogaeva E. A., Levesque G., Ikeda M., Liang Y., Chi H., Lin C., Holman K., Tsuda T. Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature. 1995 Aug 31;376(6543):775–778. doi: 10.1038/376775a0. [DOI] [PubMed] [Google Scholar]
  22. Saunders A. M., Strittmatter W. J., Schmechel D., George-Hyslop P. H., Pericak-Vance M. A., Joo S. H., Rosi B. L., Gusella J. F., Crapper-MacLachlan D. R., Alberts M. J. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. Neurology. 1993 Aug;43(8):1467–1472. doi: 10.1212/wnl.43.8.1467. [DOI] [PubMed] [Google Scholar]
  23. Selkoe D. J. The molecular pathology of Alzheimer's disease. Neuron. 1991 Apr;6(4):487–498. doi: 10.1016/0896-6273(91)90052-2. [DOI] [PubMed] [Google Scholar]
  24. Sherrington R., Rogaev E. I., Liang Y., Rogaeva E. A., Levesque G., Ikeda M., Chi H., Lin C., Li G., Holman K. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995 Jun 29;375(6534):754–760. doi: 10.1038/375754a0. [DOI] [PubMed] [Google Scholar]
  25. Sorbi S., Nacmias B., Forleo P., Piacentini S., Sherrington R., Rogaev E., St George Hyslop P., Amaducci L. Missense mutation of S182 gene in Italian families with early-onset Alzheimer's disease. Lancet. 1995 Aug 12;346(8972):439–440. doi: 10.1016/s0140-6736(95)92809-x. [DOI] [PubMed] [Google Scholar]
  26. Su J. H., Anderson A. J., Cummings B. J., Cotman C. W. Immunohistochemical evidence for apoptosis in Alzheimer's disease. Neuroreport. 1994 Dec 20;5(18):2529–2533. doi: 10.1097/00001756-199412000-00031. [DOI] [PubMed] [Google Scholar]
  27. Tanahashi H., Mitsunaga Y., Takahashi K., Tasaki H., Watanabe S., Tabira T. Missense mutation of S182 gene in Japanese familial Alzheimer's disease. Lancet. 1995 Aug 12;346(8972):440–440. doi: 10.1016/s0140-6736(95)92810-3. [DOI] [PubMed] [Google Scholar]
  28. 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]
  29. Van Broeckhoven C. Presenilins and Alzheimer disease. Nat Genet. 1995 Nov;11(3):230–232. doi: 10.1038/ng1195-230. [DOI] [PubMed] [Google Scholar]
  30. Vito P., Lacanà E., D'Adamio L. Interfering with apoptosis: Ca(2+)-binding protein ALG-2 and Alzheimer's disease gene ALG-3. Science. 1996 Jan 26;271(5248):521–525. doi: 10.1126/science.271.5248.521. [DOI] [PubMed] [Google Scholar]
  31. Wisniewski T., Palha J. A., Ghiso J., Frangione B. S182 protein in Alzheimer's disease neuritic plaques. Lancet. 1995 Nov 18;346(8986):1366–1366. doi: 10.1016/s0140-6736(95)92379-9. [DOI] [PubMed] [Google Scholar]

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

RESOURCES