Structural Mechanism of the Interaction of Alzheimer Disease Aβ Fibrils with the Non-steroidal Anti-inflammatory Drug (NSAID) Sulindac Sulfide

Elke Prade,Heiko J Bittner,Riddhiman Sarkar,Juan Miguel Lopez Del Amo,Gerhard Althoff-Ospelt,Gerd Multhaup,Peter W Hildebrand,Bernd Reif

doi:10.1074/jbc.m115.675215

Abstract

Alzheimer disease is the most severe neurodegenerative disease worldwide. In the past years, a plethora of small molecules interfering with amyloid-β (Aβ) aggregation has been reported. However, their mode of interaction with amyloid fibers is not understood. Non-steroidal anti-inflammatory drugs (NSAIDs) are known γ-secretase modulators; they influence Aβ populations. It has been suggested that NSAIDs are pleiotrophic and can interact with more than one pathomechanism. Here we present a magic angle spinning solid-state NMR study demonstrating that the NSAID sulindac sulfide interacts specifically with Alzheimer disease Aβ fibrils. We find that sulindac sulfide does not induce drastic architectural changes in the fibrillar structure but intercalates between the two β-strands of the amyloid fibril and binds to hydrophobic cavities, which are found consistently in all analyzed structures. The characteristic Asp(23)-Lys(28) salt bridge is not affected upon interacting with sulindac sulfide. The primary binding site is located in the vicinity of residue Gly(33), a residue involved in Met(35) oxidation. The results presented here will assist the search for pharmacologically active molecules that can potentially be employed as lead structures to guide the design of small molecules for the treatment of Alzheimer disease.

Highlights

The mechanism of interaction between small molecules and amyloid-␤ fibrils is unknown
Fibrillar A␤ is observed by Transmission Electron Microscopy (TEM) in the presence of the Non-steroidal anti-inflammatory drugs (NSAIDs) (Fig. 1b)
Chemical shift analysis by torsion angle likeliness obtained from shift and sequence similaritiesϩ (TALOSϩ) [69] yields secondary structural propensities that predict the presence of two ␤-strands typically observed in specific regions within A␤1–40 fibrils [44, 53, 54, 67, 70] and oligomers [71, 72]

Summary

Introduction

The mechanism of interaction between small molecules and amyloid-␤ fibrils is unknown. Results: Molecular modeling on the basis of solid-state NMR reveals that sulindac sulfide intercalates between ␤-strands of amyloid-␤ fibrils. A plethora of small molecules interfering with amyloid-␤ (A␤) aggregation has been reported. Their mode of interaction with amyloid fibers is not understood. We present a magic angle spinning solid-state NMR study demonstrating that the NSAID sulindac sulfide interacts with Alzheimer disease A␤ fibrils. We find that sulindac sulfide does not induce drastic architectural changes in the fibrillar structure but intercalates between the two ␤-strands of the amyloid fibril and binds to hydrophobic cavities, which are found consistently in all analyzed structures. The results presented here will assist the search for pharmacologically active molecules that can potentially be employed as lead structures to guide the design of small molecules for the treatment of Alzheimer disease

Objectives

Results

Conclusion