Notch-1 activation by familial Alzheimer's disease (FAD)-linked mutant forms of presenilin-1.
We prepared a cleavage site-directed antibody against Notch-1, that specifically recognized the cleaved Notch-1 intracellular domain (NICD). To assess Notch-1 processing and its nuclear localization in familial Alzheimer's disease (FAD)-linked presenilin-1 (PS-1) mutants, we overexpressed wild type, M146V, A246E, C410Y, or deltaE9 PS-1 mutant with a membrane-bound Notch-1 in a PS-1-deficient cell line. On Western blot and immunocytochemical analyses using the NICD specific antibody, M146V and A246E mutants showed the comparable levels of Notch-1 processing and nuclear localizing activities to wild type PS-1 whereas C410Y and deltaE9 mutants failed to show these activities. These results suggest that the loss or partial loss of PS-1 activities in Notch-1 proteolysis and its nuclear translocation may be irrelevant for the neuropathology of Alzheimer's disease.
Nakajima
M
M
Department of Molecular Genetics, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
Shimizu
T
T
Shirasawa
T
T
D016475:3T3 Cells; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics*; D053764:Presenilin-1; D011817:Rabbits; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D014162:Transfection; D014178:Translocation, Genetic / Q000235:genetics
D008565:Membrane Proteins; C497762:Notch1 protein, mouse; D053764:Presenilin-1; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D014157:Transcription Factors