Metabolomics Unit, Department of Pharmacology, DeBusk College of Osteopathic Medicine, Lincoln Memorial University, 6965 Cumberland Gap Parkway, Harrogate, TN 37752, USA.
Alzheimers Res Ther. 2012 Feb 1;4(1):5. doi: 10.1186/alzrt103.
Alzheimer's disease (AD) is a cognitive disorder with a number of complex neuropathologies, including, but not limited to, neurofibrillary tangles, neuritic plaques, neuronal shrinkage, hypomyelination, neuroinflammation and cholinergic dysfunction. The role of underlying pathological processes in the evolution of the cholinergic deficit responsible for cognitive decline has not been elucidated. Furthermore, generation of testable hypotheses for defining points of pharmacological intervention in AD are complicated by the large scale occurrence of older individuals dying with no cognitive impairment despite having a high burden of AD pathology (plaques and tangles). To further complicate these research challenges, there is no animal model that reproduces the combined hallmark neuropathologies of AD. These research limitations have stimulated the application of 'omics' technologies in AD research with the goals of defining biologic markers of disease and disease progression and uncovering potential points of pharmacological intervention for the design of AD therapeutics. In the case of sporadic AD, the dominant form of dementia, genomics has revealed that the ε4 allele of apolipoprotein E, a lipid transport/chaperone protein, is a susceptibility factor. This seminal observation points to the importance of lipid dynamics as an area of investigation in AD. In this regard, lipidomics studies have demonstrated that there are major deficits in brain structural glycerophospholipids and sphingolipids, as well as alterations in metabolites of these complex structural lipids, which act as signaling molecules. Peroxisomal dysfunction appears to be a key component of the changes in glycerophospholipid deficits. In this review, lipid alterations and their potential roles in the pathophysiology of AD are discussed.
阿尔茨海默病（AD）是一种认知障碍，具有多种复杂的神经病理学特征，包括但不限于神经原纤维缠结、神经炎性斑块、神经元萎缩、髓鞘减少、神经炎症和胆碱能功能障碍。导致认知能力下降的胆碱能缺陷的潜在病理过程在疾病进展中的作用尚未阐明。此外，由于大量老年人在没有认知障碍的情况下死亡，尽管他们有很高的 AD 病理负担（斑块和缠结），因此生成可用于定义 AD 中药物干预点的可测试假说变得更加复杂。为了进一步复杂化这些研究挑战，目前还没有能够复制 AD 联合标志性神经病理学的动物模型。这些研究限制刺激了“组学”技术在 AD 研究中的应用，目的是定义疾病和疾病进展的生物标志物，并揭示潜在的药物干预点，以设计 AD 治疗方法。在散发性 AD（占痴呆症的主要形式）中，基因组学揭示了载脂蛋白 E（一种脂质转运/伴侣蛋白）的 ε4 等位基因是一个易感因素。这一开创性的观察结果表明，脂质动态是 AD 研究的一个重要领域。在这方面，脂质组学研究表明，大脑结构性甘油磷脂和鞘脂存在重大缺陷，以及这些复杂结构脂质的代谢物发生改变，这些脂质代谢物作为信号分子发挥作用。过氧化物酶体功能障碍似乎是甘油磷脂缺陷变化的关键组成部分。在这篇综述中，讨论了脂质改变及其在 AD 病理生理学中的潜在作用。
