Accumulation of murine amyloidbeta42 in a gene-dosage-dependent manner in PS1 'knock-in' mice.
The establishment of an animal model with a missense mutation of presenilin-1 (PS1) is an initial step toward understanding the molecular pathogenesis of familial Alzheimer's disease (FAD) and developing therapeutic strategies for the disease. We previously described a Japanese family with FAD caused by the I213T mutation of PS1, in which typical signs and symptoms of Alzheimer's disease were observed at the age of 45 +/- 4.2 years [Hardy, J. (1997) Trends. Neurosci., 20, 154-159; Kamino, K et al. (1996) Neurosci. Lett., 208, 195-198]. Here, we report the establishment of 'knock-in' mice with the I213T PS1 missense mutation. Northern blot and reverse transcription polymerase chain reaction (RT-PCR) analyses showed that the mutated PS1 allele was expressed at the same level as the endogenous PS1 allele, demonstrating that the PS1 missense mutation was successfully introduced into the mouse PS1 locus, and therefore that the situation mimics that in FAD patients bearing PS1 missense mutations. Amyloid beta (Abeta) 42(43) peptide, but not Abeta40 peptide, accumulated in 'knock-in' mice at the age of 16-20 weeks. A clear gene-dosage effect on the increase of Abeta42(43) was observed in 'knock-in' mice: the percentage increase of Abeta42(43) in mice with mutations in both alleles was twice as high as that in mice with a single allele. These results indicate that the level of the mutated PS1 gene expression is likely to be critically involved in the production of highly amyloidogenic Abeta42(43), and confirm that PS1 mutation has an important effect on amyloid precursor protein (APP) processing, in proportion to the level of the expression of the mutant gene.
Nakano
Y
Y
Department of Environmental Medicine, Osaka University Medical School, Japan.
Kondoh
G
G
Kudo
T
T
Imaizumi
K
K
Kato
M
M
Miyazaki
J I
JI
Tohyama
M
M
Takeda
J
J
Takeda
M
M
D000483:Alleles; D016229:Amyloid beta-Peptides / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence / Q000235:genetics; D015152:Blotting, Northern; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D018628:Gene Dosage; D015870:Gene Expression / Q000502:physiology; D006579:Heterozygote; D006720:Homozygote; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice / Q000235:genetics; D008815:Mice, Inbred Strains; D020125:Mutation, Missense / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics* / Q000378:metabolism*; D053764:Presenilin-1; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000502:physiology
D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; D010446:Peptide Fragments; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42)