New class of inhibitors of amyloid-β fibril formation: Implications for the mechanism of pathogenesis in Alzheimer's disease

Hilal A. Lashuel, Dean M. Hartley, David Balakhaneh, Aneel Aggarwal, Saul Teichberg, David J E Callaway

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Abstract

The amyloid hypothesis suggests that the process of amyloid-β protein (Aβ) fibrillogenesis is responsible for triggering a cascade of physiological events that contribute directly to the initiation and progression of Alzheimer's disease. Consequently, preventing this process might provide a viable therapeutic strategy for slowing and/or preventing the progression of this devastating disease. A promising strategy to achieve prevention of this disease is to discover compounds that inhibit Aβ polymerization and deposition. Herein, we describe a new class of small molecules that inhibit Aβ aggregation, which is based on the chemical structure of apomorphine. These molecules were found to interfere with Aβ1-40 fibrillization as determined by transmission electron microscopy, Thioflavin T fluorescence and velocity sedimentation analytical ultracentrifugation studies. Using electron microscopy, time-dependent studies demonstrate that apomorphine and its derivatives promote the oligomerization of Aβ but inhibit its fibrillization. Preliminary structural activity studies demonstrate that the 10,11-dihydroxy substitutions of the D-ring of apomorphine are required for the inhibitory effectiveness of these aporphines, and methylation of these hydroxyl groups reduces their inhibitory potency. The ability of these small molecules to inhibit Aβ amyloid fibril formation appears to be linked to their tendency to undergo rapid autoxidation, suggesting that autoxidation product(s) acts directly or indirectly on Aβ and inhibits its fibrillization. The inhibitory properties of the compounds presented suggest a new class of small molecules that could serve as a scaffold for the design of more efficient inhibitors of Aβ amyloidogenesis in vivo.

Original languageEnglish
Pages (from-to)42881-42890
Number of pages10
JournalJournal of Biological Chemistry
Volume277
Issue number45
DOIs
Publication statusPublished - 8 Nov 2002
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry

Cite this

Lashuel, H. A., Hartley, D. M., Balakhaneh, D., Aggarwal, A., Teichberg, S., & Callaway, D. J. E. (2002). New class of inhibitors of amyloid-β fibril formation: Implications for the mechanism of pathogenesis in Alzheimer's disease. Journal of Biological Chemistry, 277(45), 42881-42890. https://doi.org/10.1074/jbc.M206593200