Accumulation of murine amyloid beta 42 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 strategie s for the disease. We previously described a Japanese family with FAD cause d by the I213T mutation of PS1, in which typical signs and symptoms of Alzh eimer's disease were observed at the age of 45 +/- 4.2 years [Hardy, J. (19 97) 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 p olymerase chain reaction (RT-PCR) analyses showed that the mutated PS1 alle le was expressed at the same level as the endogenous PS1 allele, demonstrat ing that the PS1 missense mutation was successfully introduced into the mou se PS1 locus, and therefore that the situation mimics that in FAD patients bearing PS1 missense mutations. Amyloid beta (A beta) 42(43) peptide, but n ot A beta 40 peptide, accumulated in 'knock-in' mice at the age of 16-20 we eks. A clear gene-dosage effect on the increase of A beta 42(43) was observ ed in 'knock-in' mice: the percentage increase of A beta 42(43) in mice wit h 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 expr ession is likely to be critically involved in the production of highly amyl oidogenic A beta 42(43), and confirm that PS1 mutation has an important eff ect on amyloid precursor protein (APP) processing, in proportion to the lev el of the expression of the mutant gene.