The Natural Product Betulinic Acid Rapidly Promotes Amyloid-β Fibril Formation at the Expense of Soluble Oligomers

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Chemistry and Biochemistry


The biochemical hallmarks of Alzheimer’s disease (AD) are the aggregates of amyloid-β (Aβ) peptide that deposit in brains of AD patients as senile plaques. The monomeric Aβ undergoes aggregation in a nucleation-dependent manner to form insoluble fibrils. Emerging evidence suggests that the low-molecular-weight aggregates called “soluble oligomers” are the primary neurotoxic agents as opposed to the fibrils. Needless to say, developing Aβ aggregation inhibitors is imperative for a meaningful progress toward AD therapy. In this report, we have explored the in vitro interactions between a natural product called betulinic acid (BA) and Aβ42 peptide. BA has found its therapeutic use in several human pathologies including cancer, HIV-related AIDS, and nervous system disorders. The results from this study indicate that BA rapidly promotes the formation of Aβ42 fibrils and, in doing so, partly circumvents the formation of potentially neurotoxic soluble oligomers. Furthermore, the promotion of fibrils by BA seems to be specific for the fibril formation “on-pathway”, and it fails to interact with aggregates that are formed outside this obligatory pathway. The unique ability of BA to promote fibrils at the expense of oligomers along with its well-known pharmacological properties make BA a potential therapeutic agent for AD.

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ACS Chemical Neuroscience





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