RESUMEN
INTRODUCTION: A hallmark of Alzheimer's disease (AD) is the presence of senile plaques composed of aggregated amyloid ß (Aß) peptides. Pathological aging (PA) is a postmortem classification that has been used to describe brains with plaque pathology similar in extent to AD, minimal cortical tau pathology, and no accompanying history of cognitive decline in the brain donor prior to death. PA may represent either a prodromal phase of AD, a benign form of Aß accumulation, or inherent individual resistance to the toxic effects of Aß accumulation. To attempt to distinguish between these possibilities we have systematically characterized Aß peptides in a postmortem series of PA, AD and non-demented control (NDC) brains. METHODS: Aß was sequentially extracted with tris buffered saline (TBS), radioimmunoprecipitation buffer (RIPA), 2% sodium dodecyl sulfate (SDS) and 70% formic acid (FA) from the pre-frontal cortex of 16 AD, eight PA, and six NDC patients. These extracts were analyzed by 1) a panel of Aß sandwich ELISAs, 2) immunoprecipitation followed by mass spectrometry (IP/MS) and 3) western blotting. These studies enabled us to asses Aß levels and solubility, peptide profiles and oligomeric assemblies. RESULTS: In almost all extracts (TBS, RIPA, 2% SDS and 70% FA) the average levels of Aß1-40, Aß1-42, Aß total, and Aßx-42 were greatest in AD. On average, levels were slightly lower in PA, and there was extensive overlap between Aß levels in individual PA and AD cases. The profiles of Aß peptides detected using IP/MS techniques also showed extensive similarity between the PA and AD brain extracts. In select AD brain extracts, we detected more amino-terminally truncated Aß peptides compared to PA patients, but these peptides represented a minor portion of the Aß observed. No consistent differences in the Aß assemblies were observed by western blotting in the PA and AD groups. CONCLUSIONS: We found extensive overlap with only subtle quantitative differences between Aß levels, peptide profiles, solubility, and SDS-stable oligomeric assemblies in the PA and AD brains. These cross-sectional data indicate that Aß accumulation in PA and AD is remarkably similar. Such data would be consistent with PA representing a prodromal stage of AD or a resistance to the toxic effects of Aß.
