MOLECULAR BASIS OF CELL AND DEVELOPMENTAL BIOLOGY
Early-onset Amyloid Deposition and Cognitive Deficits in Transgenic Mice Expressing a Double Mutant Form of Amyloid Precursor Protein 695*

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We have created early-onset transgenic (Tg) models by exploiting the synergistic effects of familial Alzheimer's disease mutations on amyloid β-peptide (Aβ) biogenesis. TgCRND8 mice encode a double mutant form of amyloid precursor protein 695 (KM670/671NL+V717F) under the control of the PrP gene promoter. Thioflavine S-positive Aβ amyloid deposits are present at 3 months, with dense-cored plaques and neuritic pathology evident from 5 months of age. TgCRND8 mice exhibit 3,200–4,600 pmol of Aβ42 per g brain at age 6 months, with an excess of Aβ42 over Aβ40. High level production of the pathogenic Aβ42 form of Aβ peptide was associated with an early impairment in TgCRND8 mice in acquisition and learning reversal in the reference memory version of the Morris water maze, present by 3 months of age. Notably, learning impairment in young mice was offset by immunization against Aβ42 (Janus, C., Pearson, J., McLaurin, J., Mathews, P. M., Jiang, Y., Schmidt, S. D., Chishti, M. A., Horne, P., Heslin, D., French, J., Mount, H. T. J., Nixon, R. A., Mercken, M., Bergeron, C., Fraser, P. E., St. George-Hyslop, P., and Westaway, D. (2000)Nature 408, 979–982). Amyloid deposition in TgCRND8 mice was enhanced by the expression of presenilin 1 transgenes including familial Alzheimer's disease mutations; for mice also expressing a M146L+L286V presenilin 1 transgene, amyloid deposits were apparent by 1 month of age. The Tg mice described here suggest a potential to investigate aspects of Alzheimer's disease pathogenesis, prophylaxis, and therapy within short time frames.

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Published, JBC Papers in Press, March 15, 2001, DOI 10.1074/jbc. M100710200

*

This work was supported in part by the Canadian Institutes for Health Research, the Ontario Mental Health Foundation, The Howard Hughes Medical Institute, Natural Sciences and Engineering Research Council of Canada, The Scottish Rite Foundation, the Alzheimer Society of Ontario, the National Institute on Aging, and the Fraternal Order of Eagles.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

FNb

Supported by Canadian Institutes for Health Research post-doctoral fellowship.

FNf

Supported by Natural Sciences and Engineering Research Council of Canada post-doctoral fellowships.