Abstract
IntroductionA hallmark of Alzheimer's disease (AD) is the presence of senile plaques composed of aggregated amyloid β (Aβ) 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 Aβ accumulation, or inherent individual resistance to the toxic effects of Aβ accumulation. To attempt to distinguish between these possibilities we have systematically characterized Aβ peptides in a postmortem series of PA, AD and non-demented control (NDC) brains.MethodsAβ 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 Aβ sandwich ELISAs, 2) immunoprecipitation followed by mass spectrometry (IP/MS) and 3) western blotting. These studies enabled us to asses Aβ levels and solubility, peptide profiles and oligomeric assemblies.ResultsIn almost all extracts (TBS, RIPA, 2% SDS and 70% FA) the average levels of Aβ1-40, Aβ1-42, Aβ total, and Aβx-42 were greatest in AD. On average, levels were slightly lower in PA, and there was extensive overlap between Aβ levels in individual PA and AD cases. The profiles of Aβ 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 Aβ peptides compared to PA patients, but these peptides represented a minor portion of the Aβ observed. No consistent differences in the Aβ assemblies were observed by western blotting in the PA and AD groups.ConclusionsWe found extensive overlap with only subtle quantitative differences between Aβ levels, peptide profiles, solubility, and SDS-stable oligomeric assemblies in the PA and AD brains. These cross-sectional data indicate that Aβ 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 Aβ.
Highlights
A hallmark of Alzheimer’s disease (AD) is the presence of senile plaques composed of aggregated amyloid b (Ab) peptides
In almost all extracts (TBS, radioimmunoprecipitation buffer (RIPA), 2% sodium dodecyl sulfate (SDS) and 70% formic acid (FA)) the average levels of Ab1-40, Ab1-42, Ab total, and Abx-42 were greatest in AD
In select AD brain extracts, we detected more aminoterminally truncated Ab peptides compared to Pathological aging (PA) patients, but these peptides represented a minor portion of the Ab observed
Summary
A hallmark of Alzheimer’s disease (AD) is the presence of senile plaques composed of aggregated amyloid b (Ab) peptides. Pathological aging (PA) patients have abundant and widespread amyloid plaques; Ab is the principle component of amyloid deposits in the AD brain. It is a secreted peptide produced through sequential cleavage of the Amyloid-b Protein Precursor (APP) by b- and g-secretases [5,6,7]. A variety of truncated and modified Ab peptides have been described (for example, 1-28, 1-29, 1-45, 2-46, 344, 3-47, 2-42, 4-42, 5-42, 6-42, 7-45, 8-42, 142Met35ox, pE3-42, pE11-42) [11,12,13,14,15,16,17,18] Of these truncated and modified forms the pyroglutamate modified forms, AbpE3-42 and AbpE11-42, have been highly investigated, as key species possibly involved in initial nucleation or seeding events [19,20,21,22]
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