Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Department of Lipid Signaling, National Center for Global Health and Medicine, Tokyo, Japan.
PLoS One. 2019 Jul 10;14(7):e0219465. doi: 10.1371/journal.pone.0219465. eCollection 2019.
Accumulation of amyloid ß (Aß) 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 Aß precursor protein transgenic mice ameliorates Aß pathology and behavioral deficits, we hypothesize that DHA may affect the fibrillization and deposition of Aß. Here we studied the effect of different types of fatty acids on Aß fibril formation by in vitro Aß 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 Aß fibrils with a unique short and curved morphology in its nucleation phase, which did not elongate further into the long and straight, mature Aß fibrils. Addition of DHA afterwards did not modify the morphology of the mature Aß(1-40) fibrils. The short and curved Aß fibrils formed in the presence of DHA did not facilitate the elongation phase of Aß fibril formation, suggesting that DHA promotes the formation of "off-pathway" conformers of Aß. Our study unravels a possible mechanism of how DHA acts protectively against the pathophysiology of Alzheimer's disease.
淀粉样 β 肽（Aβ）的积累是老年斑中淀粉样纤维的主要成分之一，是阿尔茨海默病的主要原因之一。二十二碳六烯酸（DHA）是大脑中丰富的脂肪酸，据报道对阿尔茨海默病具有保护作用，尽管 DHA 对阿尔茨海默病病理生理学的机制作用仍不清楚。由于在 Aβ前体蛋白转基因小鼠中补充 DHA 可改善 Aβ病理学和行为缺陷，我们假设 DHA 可能影响 Aβ的纤维化和沉积。在这里，我们通过体外 Aβ纤维化测定研究了不同类型脂肪酸对 Aβ纤维形成的影响。淀粉样纤维的形成包括两个步骤，即初始成核阶段和随后的延伸阶段。我们发现，不饱和脂肪酸，特别是 DHA，在其成核阶段加速了 Aβ纤维的形成，形成具有独特的短而弯曲形态的纤维，而不会进一步延伸为长而直的成熟 Aβ纤维。随后添加 DHA 不会改变成熟 Aβ（1-40）纤维的形态。在 DHA 存在下形成的短而弯曲的 Aβ纤维不会促进 Aβ纤维形成的延伸阶段，这表明 DHA 促进了 Aβ的“偏离途径”构象的形成。我们的研究揭示了 DHA 如何针对阿尔茨海默病的病理生理学发挥保护作用的可能机制。
