Krasnobaev Vladimir D, Bershatsky Yaroslav V, Bocharova Olga V, Bocharov Eduard V, Batishchev Oleg V
Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences, Leninsky Prospekt, 31, 119071 Moscow, Russia.
Research Center for Molecular Mechanisms of Aging and Age-related Diseases, Moscow Institute of Physics and Technology, Institutski per., 9, 141701 Dolgoprudny, Moscow Region, Russia.
Membranes (Basel). 2023 Jul 28;13(8):706. doi: 10.3390/membranes13080706.
One of the hallmarks of Alzheimer's disease (AD) is the accumulation of amyloid beta (Aβ) peptides in the brain. The processing of amyloid precursor protein (APP) into Aβ is dependent on the location of APP in the membrane, membrane lipid composition and, possibly, presence of lipid rafts. In this study, we used atomic force microscopy (AFM) to investigate the interaction between transmembrane fragment APP (corresponding to Aβ) and its amyloidogenic mutant L723P with membranes combining liquid-ordered and liquid-disordered lipid phases. Our results demonstrated that most of the APP is located either in the liquid-disordered phase or at the boundary between ordered and disordered phases, and hardly ever in rafts. We did not notice any major changes in the domain structure induced by APP. In membranes without cholesterol APP, and especially its amyloidogenic mutant L723P formed annular structures and clusters rising above the membrane. Presence of cholesterol led to the appearance of concave membrane regions up to 2 nm in depth that were deeper for wild type APP. Thus, membrane cholesterol regulates changes in membrane structure and permeability induced by APP that might be connected with further formation of membrane pores.
阿尔茨海默病（AD）的标志性特征之一是大脑中β-淀粉样蛋白（Aβ）肽的积累。淀粉样前体蛋白（APP）加工成Aβ取决于APP在膜中的位置、膜脂质组成以及可能存在的脂筏。在本研究中，我们使用原子力显微镜（AFM）来研究跨膜片段APP（对应于Aβ）及其淀粉样蛋白生成突变体L723P与结合了液相有序和液相无序脂质相的膜之间的相互作用。我们的结果表明，大多数APP位于液相无序相或有序相和无序相之间的边界处，很少位于脂筏中。我们没有注意到APP诱导的结构域结构有任何重大变化。在没有胆固醇的膜中，APP，尤其是其淀粉样蛋白生成突变体L723P形成环形结构和高于膜表面的聚集体。胆固醇的存在导致出现深度达2nm的凹形膜区域，野生型APP的该区域更深。因此，膜胆固醇调节由APP诱导的膜结构和通透性变化，这可能与膜孔的进一步形成有关。
