Ramsden Christopher E, Cutler Roy G, Li Xiufeng, Keyes Gregory S
Lipid Peroxidation Unit, Laboratory of Clinical Investigation, National Institute on Aging, NIH 251 Bayview Blvd., Baltimore, MD, 21224, USA.
Intramural Program of the National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, 20892, USA.
bioRxiv. 2025 Jan 18:2025.01.17.633633. doi: 10.1101/2025.01.17.633633.
As the principal lipid transporter in the human brain, apolipoprotein E (ApoE) is tasked with the transport and protection of highly vulnerable lipids required to support and remodel neuronal membranes, in a process that is dependent on ApoE receptors. Human allele variants that encode proteins differing only in the number of cysteine (Cys)-to-arginine (Arg) exchanges (ApoE2 [2 Cys], ApoE3 [1 Cys], ApoE4 [0 Cys]) comprise the strongest genetic risk factor for sporadic Alzheimer's disease (AD); however, the molecular feature(s) and resultant mechanisms that underlie these isoform-dependent effects are unknown. One signature feature of Cys is the capacity to form disulfide (Cys-Cys) bridges, which are required to form disulfide bridge-linked dimers and multimers. Here we propose the overarching hypothesis that the super-ability (for ApoE2), intermediate ability (for ApoE3) or inability (for ApoE4) to form lipid-protecting intermolecular disulfide bridges, is the central molecular determinant accounting for the disparate effects of alleles on AD risk and amyloid-β and Tau pathologies in humans. We posit that presence and abundance of Cys in human ApoE3 and ApoE2 respectively, conceal and protect vulnerable lipids transported by ApoE from peroxidation by enabling formation of ApoE homo-dimers/multimers and heteromeric ApoE complexes such as ApoE-ApoJ and ApoE-ApoD. We thus propose that the inability to form intermolecular disulfide bridges makes ApoE4-containing lipoproteins uniquely vulnerable to peroxidation and its downstream consequences. Consistent with our model, we found that brain-enriched polyunsaturated fatty acid-containing phospholipids induce disulfide-dependent dimerization and multimerization of ApoE3 and ApoE2 (but not ApoE4). By contrast, incubation with the peroxidation-resistant lipid DMPC or cholesterol alone had minimal effects on dimerization. These novel concepts and findings are integrated into our unifying model implicating peroxidation of ApoE-containing lipoproteins, with consequent ApoE receptor-ligand disruption, as the initiating molecular events that ultimately lead to AD in humans.
作为人脑中主要的脂质转运蛋白，载脂蛋白E（ApoE）负责运输和保护支持和重塑神经元膜所需的极易受损的脂质，这一过程依赖于ApoE受体。编码仅在半胱氨酸（Cys）到精氨酸（Arg）交换数量上不同的蛋白质的人类等位基因变体（ApoE2 [2个Cys]、ApoE3 [1个Cys]、ApoE4 [0个Cys]）构成了散发性阿尔茨海默病（AD）最强的遗传风险因素；然而，这些异构体依赖性效应背后的分子特征和由此产生的机制尚不清楚。Cys的一个标志性特征是形成二硫键（Cys-Cys）桥的能力，而形成二硫键桥连接的二聚体和多聚体需要这种能力。在这里，我们提出一个总体假设，即形成脂质保护分子间二硫键桥的超强能力（对于ApoE2）、中等能力（对于ApoE3）或无能力（对于ApoE4），是解释等位基因对人类AD风险以及淀粉样β蛋白和tau蛋白病理产生不同影响的核心分子决定因素。我们认为，人ApoE3和ApoE2中Cys的存在和丰度分别通过使ApoE同型二聚体/多聚体以及异源ApoE复合物（如ApoE-ApoJ和ApoE-ApoD）的形成，隐藏并保护了ApoE运输的易氧化脂质免受过氧化作用。因此，我们提出无法形成分子间二硫键桥使含ApoE4的脂蛋白特别容易受到过氧化作用及其下游后果的影响。与我们的模型一致，我们发现富含大脑的含多不饱和脂肪酸的磷脂会诱导ApoE3和ApoE2（但不是ApoE4）发生二硫键依赖性二聚化和多聚化。相比之下，单独与抗过氧化脂质二肉豆蔻酰磷脂酰胆碱（DMPC）或胆固醇孵育对二聚化的影响最小。这些新的概念和发现被整合到我们的统一模型中，该模型认为含ApoE的脂蛋白的过氧化作用以及随之而来的ApoE受体-配体破坏，是最终导致人类患AD的起始分子事件。
