Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695

Citation
Ma. Chishti et al., Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695, J BIOL CHEM, 276(24), 2001, pp. 21562-21570
Citations number
73
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
00219258 → ACNP
Volume
276
Issue
24
Year of publication
2001
Pages
21562 - 21570
Database
ISI
SICI code
0021-9258(20010615)276:24<21562:EADACD>2.0.ZU;2-H
Abstract
We have created early-onset transgenic (Tg) models by exploiting the synerg istic effects of familial Alzheimer's disease mutations on amyloid P-peptid e (Ap) biogenesis. TgCRND8 mice encode a double mutant form of amyloid prec ursor protein 695 (KM670/671NL+V717F) under the control of the PrP gene pro moter. Thioflavine S-positive AP amyloid deposits are present at 3 months, with dense-cored plaques and neuritic pathology evident from 5 months of ag e. TgCRND8 mice exhibit 3,200-4,600 pmol of A beta 42 per g brain at age 6 months, with an excess of A beta 42 over A beta 40. High level production o f the pathogenic A beta 42 form of A beta peptide was associated with an ea rly impairment in TgCRND8 mice in acquisition and learning reversal in the reference memory version of the Morris water maze, present by 3 months of a ge. Notably, learning impairment in young mice was offset by immunization a gainst A beta 42 (Janus, C., Pearson, J., McLaurin, J., Mathews, P. M., Jia ng, 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 t ransgenes including familial Alzheimer's disease mutations; for mice also e xpressing a M146L+L286V presenilin 1 transgene, amyloid deposits were appar ent by 1 month of age. The Tg mice described here suggest a potential to in vestigate aspects of Alzheimer's disease pathogenesis, prophylaxis, and the rapy within short time frames.