title: Normal brain development in PS1 hypomorphic mice with markedly reduced gamma-secretase cleavage of betaAPP.
abstract: 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.
authors.affiliation: 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
authors.forename: R
authors.initials: R
authors.lastname: Rozmahel
authors.forename: J
authors.initials: J
authors.lastname: Huang
authors.forename: F
authors.initials: F
authors.lastname: Chen
authors.forename: Y
authors.initials: Y
authors.lastname: Liang
authors.forename: V
authors.initials: V
authors.lastname: Nguyen
authors.forename: M
authors.initials: M
authors.lastname: Ikeda
authors.forename: G
authors.initials: G
authors.lastname: Levesque
authors.forename: G
authors.initials: G
authors.lastname: Yu
authors.forename: M
authors.initials: M
authors.lastname: Nishimura
authors.forename: P
authors.initials: P
authors.lastname: Mathews
authors.forename: S D
authors.initials: SD
authors.lastname: Schmidt
authors.forename: M
authors.initials: M
authors.lastname: Mercken
authors.forename: C
authors.initials: C
authors.lastname: Bergeron
authors.forename: D
authors.initials: D
authors.lastname: Westaway
authors.forename: P
authors.initials: P
authors.lastname: St George-Hyslop
mesh_terms: D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000918:Antibody Specificity; D016282:Aspartic Acid Endopeptidases; D015153:Blotting, Western; D001921:Brain / Q000033:anatomy & histology / Q000254:growth & development* / Q000473:pathology; D010450:Endopeptidases / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D018390:Gene Targeting; D005838:Genotype; D006801:Humans; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D053764:Presenilin-1; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013116:Spinal Cord / Q000473:pathology
chemical_list: D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D012333:RNA, Messenger; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse