BACE/APPV717F double-transgenic mice develop cerebral amyloidosis and inflammation.
Most of the transgenic mice generated to model Alzheimer's disease express human amyloid precursor protein (APP) mutants alone or in conjunction with presenilin mutants. We have generated a mouse model by overexpressing human BACE and human APP with the V717F mutation. The combination of a mutation at the gamma-secretase cleavage site of APP and of increased beta-secretase activity should favour the production of amyloid peptides. We analysed double BACE/APPIn and single APPIn transgenic mice at 16-18 months for amyloid load, brain histopathology and behavioural deficits. We show that overexpression of BACE induces an increase in APP CTFbeta and total brain Abeta peptides. Brain histopathology shows clearly enhanced amyloid deposits in the cortex, hippocampus and in brain vasculature when compared to single APPIn transgenic mice. Amyloid deposits are mostly diffuse and predominantly composed of Abeta(42). A strong inflammatory reaction is evidenced by the presence of microglial cells around the most mature amyloid deposits and astrocytosis over the entire cerebral cortex. At the same age, the APPIn single-transgenic mice show only very limited pathology. When assessed for their cognitive performance at 12 months, BACE/APPIn mice show impaired spatial acquisition in the Morris water maze test. However, these deficits are not greater than those observed in the APPIn single-transgenic animals.
Ozmen
Laurence
L
CNS Research, F Hoffmann-La Roche Ltd, Basel, Switzerland. laurence.ozmen@roche.com
Woolley
Marie
M
Albientz
Anita
A
Miss
Marie-Therese
MT
Nelboeck
Peter
P
Malherbe
Pari
P
Czech
Christian
C
Gruninger-Leitch
Fiona
F
Brockhaus
Manfred
M
Ballard
Theresa
T
Jacobsen
Helmut
H
D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000686:Amyloidosis / Q000235:genetics* / Q000473:pathology* / Q000523:psychology; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001522:Behavior, Animal / Q000502:physiology; D015153:Blotting, Western; D001835:Body Weight / Q000502:physiology; D004660:Encephalitis / Q000235:genetics* / Q000473:pathology* / Q000523:psychology; D010450:Endopeptidases / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse