Characterization of the Precursor Protein of the Non-Aβ Component of Senile Plaques (NACP) in the Human Central Nervous System

Abstract

A novel and highly conserved presynaptic protein has been independently described in rodents (synuclein/SYN-1), songbirds (synelfin), and humans (the precursor protein of the non-A beta component of senile plaques, NACP); a fragment of the latter has been detected in senile plaques in Alzheimer's disease (AD). We characterized the expression of NACP in human AD and non-AD brain. A subcellular fractionation study demonstrated that NACP was mainly localized to cytosolic fractions of human temporal cortex. NACP was also detectable in various membrane and vesicular fractions, suggesting that the protein was associated with membrane structures including synaptic vesicles. Pericellular immunostaining of the neuropil was observed in neocortical and limbic regions, supporting a synaptic localization. Senile plaques in AD brains were not immunoreactive, and confocal microscopy suggested a loss of NACP immunoreactivity in cored plaques. No difference was found in the amount of protein in AD and control frontal cortex, as measured by immunoblotting. PCR analysis showed that the full-length mRNA product was the major splice form in both AD and control human brains. Thus, despite the association of a hydrophobic fragment of NACP with senile plaques, our data suggest that the precursor itself is not a significant component of plaques and NACP synthesis is not substantially altered in AD. Nevertheless, the protein is an abundant component of synaptic regions prone to degeneration in AD, and may have a role in the expression or advancement of the disease.