Zentrum für Molekulare Biologie Heidelberg, University of Heidelberg, Germany.
Neurosci Lett. 2010 Sep 6;481(2):73-7. doi: 10.1016/j.neulet.2010.06.046. Epub 2010 Jun 19.
Amyloid-beta peptides (Abeta) generated by proteolysis of the beta-amyloid precursor protein (APP) by beta- and gamma-secretases play an important role in the pathogenesis of Alzheimer's disease (AD). There is mounting evidence that the lipid matrix of neuronal cell membranes plays an important role in the accumulation of Abeta peptides into senile plaques, one of the hallmarks of AD. With the aim to clarify the molecular basis of the interaction between Abeta and cellular membranes, we investigated the effects of various phospholipids (PLs) and a PL-rich diet on Abeta production. Here we show that modulation of Abeta production and Abeta42:40 ratio is not limited to individual fatty acids, rather it is the composition of the PLs of the membrane bilayer, that influences the specificity and level of the regulated intramembranous proteolysis of APP by the gamma-secretase complex. We show that Abeta levels in the conditioned media, in response to some of the PL supplements, is increased in the center and decreased on either side of a graph that resembles bell-shaped distribution. This means that the PLs have less of a tendency to produce unusually extreme effects on Abeta production in SP-C99 transfected Cos-7 cultured cells. We proposed a mechanism-based hypothesis to rationalize PLs' effects on Abeta production.
淀粉样 β 肽（Abeta）由 β-和 γ-分泌酶对β-淀粉样前体蛋白（APP）的蛋白水解产生，在阿尔茨海默病（AD）的发病机制中发挥重要作用。越来越多的证据表明，神经元细胞膜的脂质基质在 Abeta 肽积聚到老年斑中发挥重要作用，老年斑是 AD 的标志之一。为了阐明 Abeta 与细胞膜之间相互作用的分子基础，我们研究了各种磷脂（PL）和富含 PL 的饮食对 Abeta 产生的影响。在这里，我们表明 Abeta 产生和 Abeta42:40 比例的调节不仅限于单个脂肪酸，而是膜双层中 PL 的组成，影响 γ-分泌酶复合物对 APP 的调节膜内蛋白水解的特异性和水平。我们表明，在响应某些 PL 补充剂时，条件培养基中的 Abeta 水平在类似于钟形分布的图形的中心增加，而在两侧减少。这意味着在转染了 SP-C99 的 Cos-7 培养细胞中，PL 对 Abeta 产生的异常极端影响的趋势较小。我们提出了一种基于机制的假设来合理化 PL 对 Abeta 产生的影响。
