A hallmark of Alzheimer's disease (AD) is the formation of senile plaques comprised of the β-amyloid (Aβ) peptide. Aβ fibrillization is a complex nucleation-dependent process involving a variety of metastable intermediate aggregates and features the formation of inter- and intramolecular salt bridges involving lysine residues, K16 and K28. Cationic lysine residues also mediate protein-lipid interactions via association with anionic lipid headgroups. As several toxic mechanisms attributed to Aβ involve membrane interactions, the impact of acetylation on Aβ40 aggregation in the presence and absence of membranes was determined. Using chemical acetylation, varying mixtures of acetylated and nonacetylated Aβ40 were produced. With increasing acetylation, fibril and oligomer formation decreased, eventually completely arresting fibrillization. In the presence of total brain lipid extract (TBLE) vesicles, acetylation reduced the interaction of Aβ40 with membranes; however, fibrils still formed at near complete levels of acetylation. Additionally, the combination of TBLE and acetylated Aβ promoted annular aggregates. Finally, toxicity associated with Aβ40 was reduced with increasing acetylation in a cell culture assay. These results suggest that in the absence of membranes that the cationic character of lysine plays a major role in fibril formation. However, acetylation promotes unique aggregation pathways in the presence of lipid membranes.

中文翻译：

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在存在和不存在脂质膜的情况下，Aβ40的乙酰化都会改变聚集。

阿尔茨海默氏病（AD）的标志是由β-淀粉样蛋白（Aβ）肽组成的老年斑的形成。Aβ原纤维化是一个复杂的成核依赖性过程，涉及多种亚稳的中间聚集体，其特征是形成涉及赖氨酸残基K16和K28的分子间和分子内盐桥。阳离子赖氨酸残基还通过与阴离子脂质头基缔合来介导蛋白质-脂质相互作用。由于归因于Aβ的几种毒性机制涉及膜相互作用，因此确定了存在和不存在膜时乙酰化对Aβ40聚集的影响。使用化学乙酰化，产生了乙酰化和非乙酰化的Aβ40的各种混合物。随着乙酰化作用的增加，原纤维和低聚物的形成减少，最终完全阻止了原纤维化。在存在全脑脂质提取物（TBLE）囊泡的情况下，乙酰化作用会降低Aβ40与膜的相互作用。但是，原纤维仍以接近完全的乙酰化水平形成。另外，TBLE和乙酰化的Aβ的组合促进了环状聚集体。最后，在细胞培养测定中，随着乙酰化的增加，与Aβ40相关的毒性降低。这些结果表明，在没有膜的情况下，赖氨酸的阳离子特性在原纤维形成中起主要作用。然而，在脂质膜的存在下，乙酰化促进了独特的聚集途径。TBLE和乙酰化Aβ的组合促进了环状聚集体。最后，在细胞培养测定中，随着乙酰化的增加，与Aβ40相关的毒性降低。这些结果表明，在没有膜的情况下，赖氨酸的阳离子特性在原纤维形成中起主要作用。然而，在脂质膜的存在下，乙酰化促进了独特的聚集途径。TBLE和乙酰化Aβ的组合促进了环状聚集体。最后，在细胞培养测定中，随着乙酰化作用的增加，与Aβ40相关的毒性降低。这些结果表明，在没有膜的情况下，赖氨酸的阳离子特性在原纤维形成中起主要作用。然而，在脂质膜的存在下，乙酰化促进了独特的聚集途径。