Fabiani Camila, Antollini Silvia S
Instituto de Investigaciones Bioquímicas de Bahía Blanca CONICET-UNS, Bahía Blanca, Argentina.
Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca, Argentina.
Front Cell Neurosci. 2019 Jul 18;13:309. doi: 10.3389/fncel.2019.00309. eCollection 2019.
Biological membranes show lateral and transverse asymmetric lipid distribution. Cholesterol (Chol) localizes in both hemilayers, but in the external one it is mostly condensed in lipid-ordered microdomains (raft domains), together with saturated phosphatidyl lipids and sphingolipids (including sphingomyelin and glycosphingolipids). Membrane asymmetries induce special membrane biophysical properties and behave as signals for several physiological and/or pathological processes. Alzheimer's disease (AD) is associated with a perturbation in different membrane properties. Amyloid-β (Aβ) plaques and neurofibrillary tangles of tau protein together with neuroinflammation and neurodegeneration are the most characteristic cellular changes observed in this disease. The extracellular presence of Aβ peptides forming senile plaques, together with soluble oligomeric species of Aβ, are considered the major cause of the synaptic dysfunction of AD. The association between Aβ peptide and membrane lipids has been extensively studied. It has been postulated that Chol content and Chol distribution condition Aβ production and posterior accumulation in membranes and, hence, cell dysfunction. Several lines of evidence suggest that Aβ partitions in the cell membrane accumulate mostly in raft domains, the site where the cleavage of the precursor AβPP by β- and γ- secretase is also thought to occur. The main consequence of the pathogenesis of AD is the disruption of the cholinergic pathways in the cerebral cortex and in the basal forebrain. In parallel, the nicotinic acetylcholine receptor has been extensively linked to membrane properties. Since its transmembrane domain exhibits extensive contacts with the surrounding lipids, the acetylcholine receptor function is conditioned by its lipid microenvironment. The nicotinic acetylcholine receptor is present in high-density clusters in the cell membrane where it localizes mainly in lipid-ordered domains. Perturbations of sphingomyelin or cholesterol composition alter acetylcholine receptor location. Therefore, Aβ processing, Aβ partitioning, and acetylcholine receptor location and function can be manipulated by changes in membrane lipid biophysics. Understanding these mechanisms should provide insights into new therapeutic strategies for prevention and/or treatment of AD. Here, we discuss the implications of lipid-protein interactions at the cell membrane level in AD.
生物膜呈现出横向和纵向的不对称脂质分布。胆固醇（Chol）存在于两个半层中，但在外部半层中，它主要与饱和磷脂和鞘脂（包括鞘磷脂和糖鞘脂）一起浓缩在脂质有序微区（筏区）中。膜不对称性诱导了特殊的膜生物物理特性，并作为多种生理和/或病理过程的信号。阿尔茨海默病（AD）与不同的膜特性扰动有关。淀粉样β（Aβ）斑块、tau蛋白神经原纤维缠结以及神经炎症和神经退行性变是该疾病中最具特征性的细胞变化。形成老年斑的Aβ肽在细胞外的存在，以及Aβ的可溶性寡聚体，被认为是AD突触功能障碍的主要原因。Aβ肽与膜脂质之间的关联已得到广泛研究。据推测，Chol含量和Chol分布决定了Aβ的产生以及随后在膜中的积累，进而导致细胞功能障碍。几条证据表明，细胞膜中积累的Aβ主要分布在筏区，β-和γ-分泌酶切割前体AβPP也被认为发生在该区域。AD发病机制的主要后果是大脑皮层和基底前脑胆碱能通路的破坏。同时，烟碱型乙酰胆碱受体与膜特性密切相关。由于其跨膜结构域与周围脂质有广泛接触，乙酰胆碱受体的功能受其脂质微环境的影响。烟碱型乙酰胆碱受体以高密度簇的形式存在于细胞膜中，主要定位于脂质有序结构域。鞘磷脂或胆固醇组成的扰动会改变乙酰胆碱受体的定位。因此，膜脂质生物物理学的变化可以操纵Aβ的加工、Aβ的分布以及乙酰胆碱受体的定位和功能。了解这些机制应该为预防和/或治疗AD的新治疗策略提供见解。在此，我们讨论细胞膜水平上脂蛋白相互作用在AD中的意义。
