Soluble amyloid-beta buffering by plaques in Alzheimer disease dementia versus high-pathology controls.

Thomas J Esparza,David L Brody,Mihika Gangolli,Nigel J Cairns,Stephen D Ginsberg

doi:10.1371/journal.pone.0200251

Thomas J Esparza, David L Brody + Show 3 more

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https://doi.org/10.1371/journal.pone.0200251

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Abstract

An unanswered question regarding Alzheimer disease dementia (ADD) is whether amyloid-beta (Aβ) plaques sequester toxic soluble Aβ species early during pathological progression. We previously reported that the concentration of soluble Aβ aggregates from patients with mild dementia was higher than soluble Aβ aggregates from patients with modest Aβ plaque burden but no dementia. The ratio of soluble Aβ aggregate concentration to Aβ plaque area fully distinguished these groups of patients. We hypothesized that initially plaques may serve as a reservoir or sink for toxic soluble Aβ aggregates, sequestering them from other targets in the extracellular space and thereby preventing their toxicity. To initially test a generalized version of this hypothesis, we have performed binding assessments using biotinylated synthetic Aβ1–42 peptide. Aβ1-42-biotin peptide was incubated on unfixed frozen sections from non-demented high plaque pathology controls and patients with ADD. The bound peptide was measured using ELISA and confocal microscopy. We observed no quantitative difference in Aβ binding between the groups using either method. Further testing of the buffering hypothesis using various forms of synthetic and human derived soluble Aβ aggregates will be required to definitively address the role of plaque buffering as it relates to ADD.

Highlights

The relationship between Aβ plaque pathology and Alzheimer disease dementia (ADD) [1] has been a topic of considerable controversy
After binding of soluble biotinylated Aβ1–42 for 18 hours at room temperature to frozen sections followed by gentle washing in binding buffer (0.05% BSA in artificial CSF), biotinylated Aβ1–42 was retained in structures similar in size and morphology to Aβ plaques and did not appear to non- bind throughout the tissue (Fig 2A, 2B and 2D–2F)
The binding capacity of plaques for synthetic biotinylated Aβ1–42 does not appear to differentiate demented from non-demented high plaque control brains

Summary

Introduction

The relationship between Aβ plaque pathology and Alzheimer disease dementia (ADD) [1] has been a topic of considerable controversy. Soluble Aβ aggregates have been more directly linked to toxicity in vitro and in some animal model systems [2]. We recently reported that soluble Aβ aggregates (termed “oligomers” in prior publications) were elevated in aqueous brain lysates from patients with early ADD in comparison with lysates from patients with Aβ plaque pathology but no dementia [3]. Despite statistically significant differences, there was still considerable overlap between groups.

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