Normal brain development in PS1 hypomorphic mice with markedly reduced gamma-secretase cleavage of betaAPP.
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.
Rozmahel
R
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
Huang
J
J
Chen
F
F
Liang
Y
Y
Nguyen
V
V
Ikeda
M
M
Levesque
G
G
Yu
G
G
Nishimura
M
M
Mathews
P
P
Schmidt
S D
SD
Mercken
M
M
Bergeron
C
C
Westaway
D
D
St George-Hyslop
P
P
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
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