Excess of nicastrin in brain results in heterozygosity having no effect on endogenous APP processing and amyloid peptide levels in vivo

Nicastrin is an integral member of PS-complexes that perform γ-secretase cleavage of numerous type I membrane proteins including amyloid precursor protein that underlies Alzheimer's disease; thus, diminishing γ-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 γ-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 γ-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 γ-secretase cleavage, APP C-terminal fragments or β-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 γ-secretase activity as a therapeutic strategy for Alzheimer's disease.