Introduction

A 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.

Methods

Aβ 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.

Results

In 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.

Conclusions

We 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.

Background

Alzheimer's disease (AD) and a host of other neurodegenerative central nervous system (CNS) proteinopathies are characterized by the accumulation of misfolded protein aggregates. Simplistically, these aggregates can be divided into smaller, soluble, oligomeric and larger, less-soluble or insoluble, fibrillar forms. Perhaps the major ongoing debate in the neurodegenerative disease field is whether the smaller oligomeric or larger fibrillar aggregates are the primary neurotoxin. Herein, we propose an integrative hypothesis that provides new insights into how a variety of misfolded protein aggregates can result in neurodegeneration.

Results

We introduce the concept that a wide range of highly stable misfolded protein aggregates in AD and other neurodegenerative proteinopathies are recognized as non-self and chronically activate the innate immune system. This pro-inflammatory state leads to physiological senescence of CNS cells. Once CNS cells undergo physiological senescence, they secrete a variety of pro-inflammatory molecules. Thus, the senescence of cells, which was initially triggered by inflammatory stimuli, becomes a self-reinforcing stimulus for further inflammation and senescence. Ultimately, senescent CNS cells become functionally impaired and eventually die, and this neurodegeneration leads to brain organ failure.

Conclusion

This integrative hypothesis, which we will refer to as the proteinopathy-induced senescent cell hypothesis of AD and other neurodegenerative diseases, links CNS proteinopathies to inflammation, physiological senescence, cellular dysfunction, and ultimately neurodegeneration. Future studies characterizing the senescent phenotype of CNS cells in AD and other neurodegenerative diseases will test the validity of this hypothesis. The implications of CNS senescence as a contributing factor to the neurodegenerative cascade and its implications for therapy are discussed.