Strain Specific Propagation of an Amyloid Beta Oligomer in Alzheimer Disease

Document Type

Article

Publication Date

2-3-2017

Department

Chemistry and Biochemistry

School

Mathematics and Natural Sciences

Abstract

Low-molecular weight oligomers of amyloid-β (Aβ) have now been understood as the primary neurotoxic agents responsible for synaptic dysfunction and neuronal abnormalities in Alzheimer disease (AD) patients. Alongside cellular toxicity, aggregates of Aβ are also involved in proliferation and spreading of toxicity, the mechanism of which remains unclear, especially the role of oligomers in such a process. Emerging pathological evidence indicate prion-like propagation among Aβ aggregates, which may govern their ability to proliferate. Furthermore, polymorphism observed within the aggregation end products of fibrils are known to arise due to microstructural differences among the oligomers. Diversity in aggregate morphology correlates with the observed phenotypes in AD, cementing the idea that conformational strains of oligomers could be significant in phenotypic outcomes. Therefore, it is imperative to determine the ability of oligomeric strains to faithfully propagate their structure. We have identified a 12-mer of Aβ42 called, large fatty acid-derived oligomer (LFAOs), which replicate upon interacting with monomers to generate quantitative amount of LFAOs. Replication is efficient at low concentrations (< 10 μM), where LFAOs is predominantly a 12mer. At higher concentrations, LFAOs are predominantly 12-24mers that are less efficient for replication. However, 12-24mers undergo propagation towards morphologically distinct fibrils, one that is made of discrete LFAO building blocks. These results establish that strain-specific propagation of oligomeric Aβ takes places in two distinct steps of amplification and propagation in low and high concentrations of the seed, respectively. These data have opened doors to understanding underlying mechanisms of proliferation as well as strain-specific phenotypic outcomes in AD.

Publication Title

Biophysical Journal

Volume

112

Issue

3, Supplement 1

First Page

364a

Link to Full Text

Find in your library

Share

COinS