Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA.
Neurobiol Aging. 2012 Mar;33(3):628.e1-628.e14. doi: 10.1016/j.neurobiolaging.2011.04.010. Epub 2011 Jun 15.
Inheritance of the ε4 allele of apolipoprotein E (ApoE) is the only confirmed and consistently replicated risk factor for late onset Alzheimer's disease (AD). ApoE is also a key ligand for low-density lipoprotein (LDL) receptor-related protein (LRP), a major neuronal low-density lipoprotein receptor. Despite the considerable converging evidence that implicates ApoE and LRP in the pathogenesis of AD, the precise mechanism by which ApoE and LRP modulate the risk for AD remains elusive. Moreover, studies investigating expression of ApoE and LRP in AD brain have reported variable and contradictory results. To overcome these inconsistencies, we studied the mRNA expression of ApoE and LRP in the postmortem brain of persons who died at different stages of dementia and AD-associated neuropathology relative to controls by quantitative polymerase chain reaction (qPCR) and Western blotting analyses. Clinical dementia rating scores were used as a measure of dementia severity, whereas, Braak neuropathological staging and neuritic plaque density were used as indexes of the neuropathological progression of AD. ApoE and LRP mRNA expression was significantly elevated in the postmortem inferior temporal gyrus (area 20) and the hippocampus from individuals with dementia compared with those with intact cognition. In addition to their strong association with the progression of cognitive dysfunction, LRP and ApoE mRNA levels were also positively correlated with increasing neuropathological hallmarks of AD. Additionally, Western blot analysis of ApoE protein expression in the hippocampus showed that the differential expression observed at the transcriptional level is also reflected at the protein level. Given the critical role played by LRP and ApoE in amyloid beta (Aβ) and cholesterol trafficking, increased expression of LRP and ApoE may not only disrupt cholesterol homeostasis but may also contribute to some of the neurobiological features of AD, including plaque deposition.
载脂蛋白 E（ApoE）ε4 等位基因的遗传是唯一被证实且反复得到验证的晚发性阿尔茨海默病（AD）风险因素。ApoE 也是低密度脂蛋白（LDL）受体相关蛋白（LRP）的关键配体，LRP 是一种主要的神经元 LDL 受体。尽管有大量证据表明 ApoE 和 LRP 与 AD 的发病机制有关，但 ApoE 和 LRP 调节 AD 风险的确切机制仍难以捉摸。此外，研究 AD 大脑中 ApoE 和 LRP 的表达的研究报告了可变的和矛盾的结果。为了克服这些不一致，我们通过定量聚合酶链反应（qPCR）和 Western blot 分析研究了在痴呆和 AD 相关神经病理学的不同阶段死亡的人的死后大脑中 ApoE 和 LRP 的 mRNA 表达。临床痴呆评定量表评分被用作痴呆严重程度的衡量标准，而 Braak 神经病理学分期和神经原纤维缠结密度被用作 AD 神经病理学进展的指标。与认知功能正常的个体相比，痴呆个体死后下颞叶（区域 20）和海马中的 ApoE 和 LRP mRNA 表达明显升高。除了与认知功能障碍进展密切相关外，LRP 和 ApoE mRNA 水平也与 AD 的神经病理学标志物的增加呈正相关。此外，在海马体中 ApoE 蛋白表达的 Western blot 分析表明，在转录水平上观察到的差异表达也反映在蛋白水平上。鉴于 LRP 和 ApoE 在淀粉样蛋白β（Aβ）和胆固醇转运中的关键作用，LRP 和 ApoE 的表达增加不仅可能破坏胆固醇稳态，而且可能导致 AD 的一些神经生物学特征，包括斑块沉积。
