title: Excess of nicastrin in brain results in heterozygosity having no effect on endogenous APP processing and amyloid peptide levels in vivo.
abstract: Nicastrin is an integral member of PS-complexes that perform gamma-secretase cleavage of numerous type I membrane proteins including amyloid precursor protein that underlies Alzheimer's disease; thus, diminishing gamma-secretase activity by reducing levels of functional PS-complexes is suggested as a possible preventative/therapeutic avenue for the disease. One means of reducing PS-complex activity entails decreasing the levels of one or more of its components, such as nicastrin, which is fundamental to its assembly. Two previous studies detailing the effects of decreased nicastrin on gamma-secretase cleavage of APP in nicastrin heterozygous mouse fibroblast, which express relatively low levels of endogenous nicastrin compared to neurons, were contradictory. One report documented a 50% reduction in gamma-secretase cleavage of APP while the second showed markedly higher levels of this activity. Here we report that brains of heterozygous nicastrin mice show no difference in levels of APP gamma-secretase cleavage, APP C-terminal fragments or beta-amyloid peptides, compared to wild-type. This result is explained by the levels of nicastrin protein and functional presenilin complexes being similar between the heterozygous and wild-type brains, though nicastrin mRNA levels were diminished appropriately in the former. These in vivo results indicate that nicastrin mRNA and its immature protein are likely in overabundance in neurons and not limiting for assembly of PS-complexes, and that a 50% reduction of its mRNA or protein production would not affect APP processing, in contrast to fibroblast. Thus, partial reduction (maintaining a level above 50% of normal) of brain nicastrin would likely not be efficacious in reducing functional PS-complexes and gamma-secretase activity as a therapeutic strategy for Alzheimer's disease.
authors.affiliation: Department of Biochemistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: Sonya
authors.initials: S
authors.lastname: Brijbassi
authors.forename: Zareen
authors.initials: Z
authors.lastname: Amtul
authors.forename: Susan
authors.initials: S
authors.lastname: Newbigging
authors.forename: David
authors.initials: D
authors.lastname: Westaway
authors.forename: Peter
authors.initials: P
authors.lastname: St George-Hyslop
authors.forename: Richard F
authors.initials: RF
authors.lastname: Rozmahel
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002462:Cell Membrane / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D006579:Heterozygote; D046911:Macromolecular Substances / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D053764:Presenilin-1 / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins; D053764:Presenilin-1; D012333:RNA, Messenger; C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases