Characterization of the unique In Vitro effects of unsaturated fatty acids on the formation of amyloid β fibrils

Accumulation of amyloid s (As) peptides, the major component of amyloid fibrils in senile plaques, is one of the main causes of Alzheimer’s disease. Docosahexaenoic acid (DHA) is a fatty acid abundant in the brain, and is reported to have protective effects against Alzheimer’s disease, although the mechanistic effects of DHA against Alzheimer’s pathophysiology remain unclear. Because dietary supplementation of DHA in As precursor protein transgenic mice ameliorates As pathology and behavioral deficits, we hypothesize that DHA may affect the fibrillization and deposition of As. Here we studied the effect of different types of fatty acids on As fibril formation by in vitro As fibrillization assay. Formation of amyloid fibrils consists of two steps, i.e., the initial nucleation phase and the following elongation phase. We found that unsaturated fatty acids, especially DHA, accelerated the formation of As fibrils with a unique short and curved morphology in its nucleation phase, which did not elongate further into the long and straight, mature As fibrils. Addition of DHA afterwards did not modify the morphology of the mature As(1–40) fibrils. The short and curved As fibrils formed in the presence of DHA did not facilitate the elongation phase of As fibril formation, suggesting that DHA promotes the formation of “off-pathway” conformers of As. Our study unravels a possible mechanism of how DHA acts protectively against the pathophysiology of Alzheimer’s disease.