Normal brain development in PS1 hypomorphic mice with markedly reduced γ-secretase cleavage of βAPP

Presenilin 1-null mice die at birth from brain and skeletal developmental deformities due to disrupted Notch signaling. Presenilin 1-null mice also have severely reduced γ-secretase cleavage of βAPP. The assumption has been that facilitation of Notch signaling and βAPP processing by presenilin 1 are analogous functions. Here we describe a presenilin 1-targetted mouse model that expresses extremely low levels (not, vert, similar1% of normal) of mutant PS1-M146L. Homozygous mice have significantly reduced viability due to a Notch-like phenotype. The animals that survive have severe axial skeletal deformities and markedly diminished γ-secretase activity and accumulation of βAPP-C100, but no obvious abnormalities in brain development. These results suggest that, in mice, a marked reduction of PS1-facilitated γ-secretase activity is not detrimental to normal brain development.