Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695.
We have created early-onset transgenic (Tg) models by exploiting the synergistic effects of familial Alzheimer's disease mutations on amyloid beta-peptide (Abeta) 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 Abeta 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 Abeta42 per g brain at age 6 months, with an excess of Abeta42 over Abeta40. High level production of the pathogenic Abeta42 form of Abeta 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 Abeta42 (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.
Centre for Research in Neurodegenerative Diseases, the Department of Laboratory Medicine, Division of Neurology, University Health Network, University of Toronto, Toronto, Ontario M5S 3H2, Canada.
M A
MA
Chishti
D S
DS
Yang
C
C
Janus
A L
AL
Phinney
P
P
Horne
J
J
Pearson
R
R
Strome
N
N
Zuker
J
J
Loukides
J
J
French
S
S
Turner
G
G
Lozza
M
M
Grilli
S
S
Kunicki
C
C
Morissette
J
J
Paquette
F
F
Gervais
C
C
Bergeron
P E
PE
Fraser
G A
GA
Carlson
P S
PS
George-Hyslop
D
D
Westaway
D000375:Aging; D019943:Amino Acid Substitution; D000682:Amyloid / Q000032:analysis / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000032:analysis / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000686:Amyloidosis / Q000235:genetics* / Q000473:pathology / Q000523:psychology; D000818:Animals; D001921:Brain / Q000254:growth & development / Q000473:pathology*; D003072:Cognition Disorders / Q000235:genetics* / Q000473:pathology; D003433:Crosses, Genetic; D005260:Female; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D011401:Promoter Regions, Genetic; D015183:Restriction Mapping
D000682:Amyloid; D016564:Amyloid beta-Protein Precursor