ABSTRACT
Studies conducted in cell culture indicate that the gamma-secretase involved in amyloid beta-formation and Notch signaling is a multisubunit aspartic protease. Little is known, however, of the structure, function, or localization of gamma-secretase in the adult brain, or possible effects of familial Alzheimer's disease (FAD)-causing mutations on the brain protease. We report here that mouse brain contains a complex composed of gamma-secretase subunits presenilin-1 N-terminal fragment, presenilin-1 C-terminal fragment, Nicastrin, Aph-1a and Pen-2. A homozygous FAD-linked Presenilin-1 knock-in mutation does not alter relative subunit levels. Immunocytochemical localization of gamma-secretase subunits revealed overlapping but distinct regional and subcellular distributions. All subunits are expressed throughout the neuraxis predominantly in neurons, and are present in axons. Their distributions and levels of expression are unaffected by mutant presenilin-1. In a presenilin-1/amyloid precursor protein double knock-in mouse, subunits are associated with plaques, but are expressed at similar levels in amyloid-rich and -poor regions. gamma-Secretase subunits are distributed much more extensively than circumscribed amyloid deposits, suggesting the importance of other factors for localized amyloid deposition. These results indicate a widespread neuronal function for gamma-secretase in the adult brain, and suggest the pathogenic mechanism of FAD-linked mutations does not involve alterations in the composition, expression or brain distribution of the protease. The subcellular localization of gamma-secretase subunits is consistent with a nerve terminal source for amyloid aggregates.
