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

Abstract

Accumulation of amyloid β (Aβ) 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 Aβ precursor protein transgenic mice ameliorates Aβ pathology and behavioral deficits, we hypothesize that DHA may affect the fibrillization and deposition of Aβ. Here we studied the effect of different types of fatty acids on Aβ fibril formation by in vitro Aβ 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 Aβ fibrils with a unique short and curved morphology in its nucleation phase, which did not elongate further into the long and straight, mature Aβ fibrils. Addition of DHA afterwards did not modify the morphology of the mature Aβ(1-40) fibrils. The short and curved Aβ fibrils formed in the presence of DHA did not facilitate the elongation phase of Aβ fibril formation, suggesting that DHA promotes the formation of "off-pathway" conformers of Aβ. Our study unravels a possible mechanism of how DHA acts protectively against the pathophysiology of Alzheimer's disease.