Attenuation of [beta]-Amyloid Toxicity In Vitro and In Vivo by Accelerated Aggregation

Accumulation and aggregation of [beta]-amyloid (A[beta]) peptides result in neuronal death, leading to cognitive dysfunction in Alzheimer's disease. The self-assembled A[beta] molecules form various intermediate aggregates including oligomers that are more toxic to neurons than the mature aggregates, including fibrils. Thus, one strategy to alleviate A[beta] toxicity is to facilitate the conversion of A[beta] intermediates to larger aggregates such as fibrils. In this study, we designed a peptide named A3 that significantly enhanced the formation of amorphous aggregates of A[beta] by accelerating the aggregation kinetics. Thioflavin T fluorescence experiments revealed an accelerated aggregation of A[beta] monomers, accompanying reduced A[beta] cytotoxicity. Transgenic Caenorhabditis elegans over-expressing amyloid precursor protein exhibited paralysis due to the accumulation of A[beta] oligomers, and this phenotype was attenuated by feeding the animals with A3 peptide. These findings suggest that the A[beta] aggregation-promotion effect can potentially be useful for developing strategies to reduce A[beta] toxicity.