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

Rozmahel, R; Huang, J; Chen, F; Liang, Y; Nguyen, V; Ikeda, M; Levesque, G; Yu, G; Nishimura, M; Mathews, P; Schmidt, S D; Mercken, M; Bergeron, C; Westaway, D; St George-Hyslop, P

Rozmahel, R; Huang, J; Chen, F; Liang, Y; Nguyen, V; Ikeda, M; Levesque, G; Yu, G; Nishimura, M; Mathews, P; Schmidt, S D; Mercken, M; Bergeron, C; Westaway, D; St George-Hyslop, P.

Afiliación

Rozmahel R; Centre for Research in Neurodegenerative Diseases, Depts. of Pharmacology, Medicine, Laboratory Medicine and Pathobiology, University of Toronto, M5S 1A1, Toronto, Ontario, Canada. richard.rozmahel@utoronto.ca

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

Article en En | MEDLINE | ID: mdl-11804702

RESUMEN

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.

Asunto(s)

Precursor de Proteína beta-Amiloide/metabolismo; Encéfalo/crecimiento & desarrollo; Endopeptidasas/metabolismo; Proteínas de la Membrana/deficiencia; Proteínas de la Membrana/genética; Secretasas de la Proteína Precursora del Amiloide; Precursor de Proteína beta-Amiloide/genética; Animales; Especificidad de Anticuerpos; Ácido Aspártico Endopeptidasas; Western Blotting; Encéfalo/anatomía & histología; Encéfalo/patología; Ensayo de Inmunoadsorción Enzimática; Marcación de Gen; Genotipo; Humanos; Ratones; Ratones Transgénicos; Mutación/genética; Fenotipo; Presenilina-1; ARN Mensajero/biosíntesis; ARN Mensajero/genética; Médula Espinal/patología

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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Endopeptidasas / Encéfalo / Precursor de Proteína beta-Amiloide / Proteínas de la Membrana Límite: Animals / Humans Idioma: En Revista: Neurobiol Aging Año: 2002 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos

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