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Letters to Nature
Nature 373, 523 - 527 (09 February 1995); doi:10.1038/373523a0

Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein

Dora Games*, David Adams, Ree Alessandrini, Robin Barbour*, Patricia Borthelette, Catherine Blackwell, Tony Carr*, James Clemens§, Thomas Donaldson, Frances Gillespie, Terry Guido*, Stephanie Hagopian, Kelly Johnson-Wood*, Karen Khan*, Mike Lee*, Paul Leibowitz, Ivan Lieberburg*, Sheila Little§, Eliezer Masliah, Lisa McConlogue*, Martin Montoya-Zavala, Lennart Muckestar, Lisa Paganini*, Elizabeth Penniman, Mike Power*, Dale Schenk*, Peter Seubert*, Ben Snyder, Ferdie Soriano*, Hua Tan*, James Vitale, Sam Wadsworth, Ben Wolozin** & Jun Zhao*

*Athena Neurosciences, Inc., 800 Gateway Boulevard, South San Francisco, California 94080, USA
Exemplar Corporation, One Innovation Drive, Worcester, Massachusetts 01605, USA
§Lilly Research Laboratories, Indianapolis, Indiana 46285, USA
starThe Scripps Research Institute, Department of Neuropharmacology, 10666 North Torrey Pines Road, La Jolla, California 92037, USA
Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA
**Laboratory of Clinical Science, National Institute of Mental Health, 9000 Rockville Pike, 1013D41, Bethesda, Maryland 20892, USA
Present addresses: Department of Biology and Biotechnology, Worcester Polytechnic Institute, 100 Institute Road, Worcester, MA 01609, USA (DA); Genzyme Corporation, One Mountain Road, Framingham, MA 01701, USA (P.B.); University of Massachusetts, Department of Veterin-arian and Animal Sciences, Amherst, MA 01003, USA (C.B.); Molecular Therapeutics Inc, 400 Morgan Lane, West Haven, CT 06516, USA (T.D.); Transkaryotic Therapies Inc., 195 Albany Street, Cambridge, MA 02139, USA (F.G.); Joint Program in Neonatology, Children's Hospital, Enders, Rm 950, 300 Longwood Avenue, Boston, MA 02115, USA (S.H.); Innovir Laboratories Inc., 510 East 73 Street, New York, NY 10022, USA (P.L.); Alteon Inc., 170 Williams Drive, Ramsey, NJ 07446, USA (M.M.-Z.); Millennium Pharmaceuticals Inc., 640 Memorial Drive, Cam-bridge, MA 02139, USA (J.V.).
To whom correspondence should be addressed.

ALZHEIMER'S disease (AD) is the most common cause of progressive intellectual failure in aged humans. AD brains contain numerous amyloid plaques surrounded by dystrophic neurites, and show profound synaptic loss, neurofibrillary tangle formation and gliosis. The amyloid plaques are composed of amyloid β-peptide (Aβ), a 40–42-amino-acid fragment of the β-amyloid precursor protein (APP)1. A primary pathogenic role for APP/Aβ is sug-gested by missense mutations in APP that are tightly linked to autosomal dominant forms of AD2,3. A major obstacle to elucidating and treating AD has been the lack of an animal model. Animals transgenic for APP have previously failed to show extensive AD-type neuropathology4-10, but we now report the production of transgenic mice that express high levels of human mutant APP (with valine at residue 717 substituted by phenylalanine) and which progressively develop many of the pathological hallmarks of AD, including numerous extracellular thioflavin S-positive Aβ deposits, neuritic plaques, synaptic loss, astrocytosis and microgliosis. These mice support a primary role for APP/Aβ in the genesis of AD and could provide a preclinical model for testing therapeutic drugs.

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References

1. Selkoe, D. J. A. Rev. Neurosci. 17, 489−517 (1994). | Article | ISI | ChemPort |
2. Hardy, J. Clin. geriatr. Med. 10, 239−247 (1994). | PubMed | ChemPort |
3. Mann, D. M. A. et al. Neurodegeneration 1, 201−215 (1992).
4. Quon, D. et al. Nature 352, 239−241 (1991). | Article | PubMed | ISI | ChemPort |
5. Sanhu, F. A., Salim, M. & Zain, S. B. J. biol. Chem. 266, 21331−21334 (1991). | PubMed | ISI | ChemPort |
6. Lamb, B. T. et al. Nature Genet. 5, 22−30 (1993). | Article | PubMed | ISI | ChemPort |
7. Pearson, B. E. & Choi, T. K. Proc. natn. acad. Sci. U.S.A. 90, 10578−10582 (1993). | ChemPort |
8. Mucke, L. et al. Brain Res. 666, 151−167 (1994). | Article | PubMed | ISI | ChemPort |
9. McConlogue, L. et al. Neurobiol. Aging 15, S12 (1994).
10. Higgins, L. S. et al. Ann. Neurol. 35, 598−607 (1994). | Article | PubMed | ISI | ChemPort |
11. Sasahara, M. et al. Cell 64, 217−227 (1991). | Article | PubMed | ISI | ChemPort |
12. Murrell, J. et al. Science 254, 97−99 (1991). | PubMed | ISI | ChemPort |
13. Seubert, P. et al. Nature 359, 325−327 (1992). | Article | PubMed | ISI | ChemPort |
14. Cork, L. C. et al. J. Neuropath. exp. Neurol. 47, 629−641 (1988). | PubMed | ChemPort |
15. Masliah, E. et al. Am. J. Path. 138, 235−246 (1991). | PubMed | ChemPort |
16. Suzuki, N. et al. Science 264, 1336−1340 (1994). | PubMed | ISI | ChemPort |
17. Roher, A. et al. J. biol. Chem. 269, 3072−3083 (1993).
18. Maggio, J. E. et al. Proc. natn Acad. Sci. U.S.A. 89, 5462−5466 (1992). | ChemPort |
19. Hogan, B., Constantini, F. & Lacey, E. in Manipulating the Mouse Embryo: A Laboratory Manual (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 1986).
20. Chomazynski, P. & Sacchi, N. Analyt. Biochem. 162, 156−159 (1987). | PubMed |
21. Wang, A. M. et al. Proc. natn. Acad. Sci. U.S.A. 86, 9717−9721 (1989). | ChemPort |
22. Oltersdorf, T. et al. J. biol. Chem. 265, 4492−4497 (1990). | PubMed | ChemPort |
23. Arai, H. et al. Proc. natn. Acad. Sci. U.S.A. 87, 2249−2253 (1990). | ChemPort |
24. Tamaoka, A. et al. Proc. natn. Acad. Sci. U.S.A. 89, 1345−1349 (1992). | ChemPort |
25. Games, D. et al. Neurobiol. Aging 13, 569−576 (1992). | Article | PubMed | ChemPort |
26. Saido, T. C. et al. J. biol. Chem. 269, 15253−15257 (1994). | PubMed | ChemPort |
27. Dickson, D. W. et al. Acta neuropath. 79, 486−493 (1990). | PubMed | ChemPort |
28. Masliah, E. et al. J. Neuropath. exp. Neurol. 52, 619−632 (1993). | PubMed | ISI | ChemPort |
29. Masliah, E. et al. Acts neuropath. 81, 428−433 (1991). | ChemPort |



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