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Neurobiol Aging. 2002 Mar-Apr;23(2):187-94.

Normal brain development in PS1 hypomorphic mice with markedly reduced gamma-secretase cleavage of betaAPP.

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Centre for Research in Neurodegenerative Diseases, Depts. of Pharmacology, Medicine, Laboratory Medicine and Pathobiology, University of Toronto, M5S 1A1, Toronto, Ontario, Canada.


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 gamma-secretase cleavage of betaAPP. The assumption has been that facilitation of Notch signaling and betaAPP processing by presenilin 1 are analogous functions. Here we describe a presenilin 1-targetted mouse model that expresses extremely low levels ( approximately 1% 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 gamma-secretase activity and accumulation of betaAPP-C100, but no obvious abnormalities in brain development. These results suggest that, in mice, a marked reduction of PS1-facilitated gamma-secretase activity is not detrimental to normal brain development.

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