Small Molecule Inhibitors of Aggregation Indicate That Amyloid β Oligomerization and Fibrillization Pathways Are Independent and Distinct*

By Mihaela Necula, R. Kayed, S. Milton, C. Glabe. Journal of Biological Chemistry, 2007

697 citations recorded by the source corpus.

Alzheimer disease is characterized by the abnormal aggregation of amyloid β peptide into extracellular fibrillar deposits known as amyloid plaques. Soluble oligomers have been observed at early time points preceding fibril formation, and these oligomers have been implicated as the primary pathological species rather than the mature fibrils. A significant issue that remains to be resolved is whether amyloid oligomers are an obligate intermediate on the pathway to fibril formation or represent an alternate assembly pathway that may or may not lead to fiber formation. To determine whether amyloid β oligomers are obligate intermediates in the fibrillization pathway, we characterized the mechanism of action of amyloid β aggregation inhibitors in terms of oligomer and fibril formation. Based on their effects, the small molecules segregated into three distinct classes: compounds that inhibit oligomerization but not fibrillization, compounds that inhibit fibrillization but not oligomerization, and compounds that inhibit both. Several compounds selectively inhibited oligomerization at substoichiometric concentrations relative to amyloid β monomer, with some active in the low nanomolar range. These results indicate that oligomers are not an obligate intermediate in the fibril formation pathway. In addition, these data suggest that small molecule inhibitors are useful for clarifying the mechanisms underlying protein aggregation and may represent potential therapeutic agents that target fundamental disease mechanisms.

Subfields: Molecular Biology, Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/1cb0fffcaa67f0e411fbae672ced8e6948821b2a

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In Molecular Biology

In Neurology

Vladimir N Uversky

In Physiology

Citations in the corpus

Α-synuclein misfolding and Parkinson's disease. (2012, background): “This has been also shown for many individual small molecules such as methylene blue [373,374], polyphenols [371, 375–377], and many others.”
Alzheimer’s Disease and the β-Amyloid Peptide (2010, neutral): “There is evidence [101] that soluble oligomer formation and ﬁbril formation may be different pathways, although mechanistically both processes have to pass through multi-meric stages.”
Aggregation of therapeutic proteins (2017, background): “The terms proportional to a 23 and a 33 are due to contributions, respectively, from solvent averaged protein – cosolute (23) and cosolute – cosolute (33) interactions other than steric repulsions.”