Department of Neurology, University of Bonn, Sigmund-Freud-Str, 25, 53127, Bonn, Germany.
Mol Neurodegener. 2013 Oct 22;8:34. doi: 10.1186/1750-1326-8-34.
Alzheimer's disease (AD) is neuropathologically characterized by the combined occurrence of extracellular β-amyloid plaques and intracellular neurofibrillary tangles in the brain. While plaques contain aggregated forms of the amyloid β-peptide (Aβ), tangles are formed by fibrillar forms of the microtubule associated protein tau. All mutations identified so far to cause familial forms of early onset AD (FAD) are localized close to or within the Aβ domain of the amyloid precursor protein (APP) or in the presenilin proteins that are essential components of a protease complex involved in the generation of Aβ. Mutations in the tau gene are not associated with FAD, but can cause other forms of dementia. The genetics of FAD together with biochemical and cell biological data, led to the formulation of the amyloid hypothesis, stating that accumulation and aggregation of Aβ is the primary event in the pathogenesis of AD, while tau might mediate its toxicity and neurodegeneration.The generation of Aβ involves sequential proteolytic cleavages of the amyloid precursor protein (APP) by enzymes called β-and γ-secretases. Notably, APP itself as well as the secretases are integral membrane proteins. Thus, it is very likely that membrane lipids are involved in the regulation of subcellular transport, activity, and metabolism of AD related proteins.Indeed, several studies indicate that membrane lipids, including cholesterol and sphingolipids (SLs) affect Aβ generation and aggregation. Interestingly, APP and other AD associated proteins, including β-and γ-secretases can, in turn, influence lipid metabolic pathways. Here, we review the close connection of cellular lipid metabolism and AD associated proteins and discuss potential mechanisms that could contribute to initiation and progression of AD.
阿尔茨海默病（AD）在神经病理学上的特征是脑内细胞外β-淀粉样斑块和细胞内神经原纤维缠结的共同发生。虽然斑块含有聚集形式的淀粉样β肽（Aβ），但缠结是由微管相关蛋白 tau 的纤维形式形成的。迄今为止发现的导致早发性家族性 AD（FAD）的所有突变都定位于淀粉样前体蛋白（APP）的 Aβ 结构域内或附近，或定位于构成参与 Aβ 生成的蛋白酶复合物的必需成分的早老素蛋白内。tau 基因突变与 FAD 无关，但可引起其他形式的痴呆。FAD 的遗传学以及生化和细胞生物学数据导致了淀粉样假说的提出，该假说指出 Aβ 的积累和聚集是 AD 发病机制中的主要事件，而 tau 可能介导其毒性和神经退行性变。Aβ 的产生涉及淀粉样前体蛋白（APP）被称为β-和γ-分泌酶的酶的顺序蛋白水解切割。值得注意的是，APP 本身以及分泌酶都是完整的膜蛋白。因此，膜脂质很可能参与 AD 相关蛋白的亚细胞运输、活性和代谢的调节。事实上，几项研究表明，包括胆固醇和鞘脂（SL）在内的膜脂质会影响 Aβ 的产生和聚集。有趣的是，APP 和其他 AD 相关蛋白，包括β-和γ-分泌酶，反过来也可以影响脂质代谢途径。在这里，我们回顾了细胞脂质代谢与 AD 相关蛋白的密切联系，并讨论了可能有助于 AD 起始和进展的潜在机制。
