Aromatic Small Molecules Remodel Toxic Soluble Oligomers of Amyloid β through Three Independent Pathways

Ali Reza A Ladiwala,Jonathan S Dordick,Peter M Tessier

doi:10.1074/jbc.m110.173856

Ali Reza A Ladiwala, Jonathan S Dordick + Show 1 more

Open Access

https://doi.org/10.1074/jbc.m110.173856

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Abstract

In protein conformational disorders ranging from Alzheimer to Parkinson disease, proteins of unrelated sequence misfold into a similar array of aggregated conformers ranging from small oligomers to large amyloid fibrils. Substantial evidence suggests that small, prefibrillar oligomers are the most toxic species, yet to what extent they can be selectively targeted and remodeled into non-toxic conformers using small molecules is poorly understood. We have evaluated the conformational specificity and remodeling pathways of a diverse panel of aromatic small molecules against mature soluble oligomers of the Aβ42 peptide associated with Alzheimer disease. We find that small molecule antagonists can be grouped into three classes, which we herein define as Class I, II, and III molecules, based on the distinct pathways they utilize to remodel soluble oligomers into multiple conformers with reduced toxicity. Class I molecules remodel soluble oligomers into large, off-pathway aggregates that are non-toxic. Moreover, Class IA molecules also remodel amyloid fibrils into the same off-pathway structures, whereas Class IB molecules fail to remodel fibrils but accelerate aggregation of freshly disaggregated Aβ. In contrast, a Class II molecule converts soluble Aβ oligomers into fibrils, but is inactive against disaggregated and fibrillar Aβ. Class III molecules disassemble soluble oligomers (as well as fibrils) into low molecular weight species that are non-toxic. Strikingly, Aβ non-toxic oligomers (which are morphologically indistinguishable from toxic soluble oligomers) are significantly more resistant to being remodeled than Aβ soluble oligomers or amyloid fibrils. Our findings reveal that relatively subtle differences in small molecule structure encipher surprisingly large differences in the pathways they employ to remodel Aβ soluble oligomers and related aggregated conformers.

Highlights

Our findings strongly argue that Class IA and III molecules remodel A␤ fibrils through the same pathways they employ to remodel soluble oligomers, and Class IB and II molecules are selective for remodeling A␤ soluble oligomers
A␤ Non-toxic Oligomers Are More Resistant to Remodeling Than Soluble Oligomers or Fibrils—We recently identified an oligomeric form of A␤ that is morphologically indistinguishable from A␤ soluble oligomers, yet these oligomers are nontoxic and possess a collection of biochemical properties not found in other A␤ conformers [12]
Even in the absence of small molecule antagonists, we have reported previously that A␤ soluble oligomers are not committed to a single nucleation pathway [12]

Summary

Introduction

The development of several conformation-specific antibodies capable of selectively detecting aggregated conformers ranging from intermediates (e.g. soluble oligomers [32,33,34], fibrillar oligomers [21], and annular protofibrils [35]) to end products (i.e. fibrils [36, 37]) of amyloid assembly have been critical to overcoming such challenges Such conformation-specific antibodies and related biochemical assays are beginning to illuminate pathways employed by aromatic small molecules to remodel mature soluble oligomers of A␤ and other disease-associated proteins (29 –31, 38). Multiple polyphenols have been found recently to convert mature soluble oligomers of A␤ and Tau into offpathway, SDS-resistant aggregates that are non-toxic [12, 31, 39] These and related studies suggest that conversion. We demonstrate that diverse aromatic small molecules utilize three independent pathways to remodel mature A␤ soluble oligomers into benign conformers with highly dissimilar biochemical properties

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