ABSTRACT
Alzheimer's disease (AD) is an age-related disorder that results in progressive cognitive impairment and memory loss. Deposition of amyloid ß (Aß) peptides in senile plaques is a hallmark of AD. γ-secretase produces Aß peptides, mostly as the soluble Aß40 with fewer insoluble Aß42 peptides. Rare, early-onset AD (EOAD) occurs in individuals under 60 years of age. Most EOAD cases are due to unknown genetic causes, but a subset is due to mutations in the genes encoding the amyloid precursor protein that is processed into Aß peptides or the presenilins (PS1 and PS2) that process APP. PS1 interacts with the epsilon isoform of glial fibrillary acidic protein (GFAPÉ), a protein found in the subventricular zone of the brain. We have found that GFAPÉ interacts with the telomere protection factor RAP1 (TERF2IP). RAP1 can also interact with PS1 alone or with GFAPÉ in vitro. Our data show that the nuclear protein RAP1 has an extratelomeric role in the cytoplasm through its interactions with GFAPÉ and PS1. GFAPÉ coprecipitated with RAP1 from human cell extracts. RAP1, GFAPÉ, and PS1 all colocalized in human SH-SY5Y cells. Using a genetic model of the γ-secretase complex in Saccharomyces cerevisiae, RAP1 increased γ-secretase activity, and this was potentiated by GFAPÉ. Our studies are the first to connect RAP1 with an age-related disorder.