Drouet B, Fifre A, Pinçon-Raymond M, Vandekerckhove J, Rosseneu M, Guéant J L, Chambaz J, Pillot T
INSERM U-505, Université Pierre et Marie Curie, Paris, France.
J Neurochem. 2001 Jan;76(1):117-27. doi: 10.1046/j.1471-4159.2001.00047.x.
Although the genetic link between the epsilon 4 allele of apolipoprotein E (apoE) and Alzheimer's disease (AD) is well established, the apoE isoform-specific activity underlying this correlation remains unclear. We have recently characterized the interaction of the soluble the amyloid-beta peptide (A beta) with model membrane and demonstrated that non-fibrillar A beta peptide, including N-terminal truncated forms of A beta, induced apoptotic cell death in primary rat cortical neurones in vitro. To further investigate the potential interaction between apoE and A beta in the pathogenesis of AD, we have determined the effect of apoE isoforms on the neurotoxicity of non-fibrillar A beta peptides. We demonstrate here that the apoE2 and E3 isoforms protect cortical neurones against apoptotic cell death induced by a non-fibrillar form of the A beta(1-40), A beta(12-42), A beta(29-40) and A beta(29-42) peptides, whereas apoE4 had no effect. This effect involves the formation of stable complexes between apoE and the C-terminal domain (e.g. amino acids 29-40) of A beta(1-40). Interestingly, apoE had no effect on the toxicity induced by aggregated A beta peptides, suggesting a lack of interaction between apoE and amyloid fibrils. Our results provide evidence that interaction with the C-terminal domain of A beta, apoE2 and E3, but not apoE4, inhibits the interactions of the non-fibrillar A beta peptide with the plasma membrane of neurones, A beta peptide aggregation and subsequent neurotoxicity.
尽管载脂蛋白E（apoE）的ε4等位基因与阿尔茨海默病（AD）之间的遗传联系已得到充分证实，但这种相关性背后的apoE异构体特异性活性仍不清楚。我们最近表征了可溶性淀粉样β肽（Aβ）与模型膜的相互作用，并证明非纤维状Aβ肽，包括Aβ的N端截短形式，在体外可诱导原代大鼠皮层神经元凋亡性细胞死亡。为了进一步研究apoE与Aβ在AD发病机制中的潜在相互作用，我们确定了apoE异构体对非纤维状Aβ肽神经毒性的影响。我们在此证明，apoE2和E3异构体可保护皮层神经元免受由非纤维状形式的Aβ（1-40）、Aβ（12-42）、Aβ（29-40）和Aβ（29-42）肽诱导的凋亡性细胞死亡，而apoE4则没有作用。这种作用涉及apoE与Aβ（1-40）的C端结构域（如氨基酸29-40）之间形成稳定的复合物。有趣的是，apoE对聚集的Aβ肽诱导的毒性没有影响，这表明apoE与淀粉样纤维之间缺乏相互作用。我们的结果提供了证据，即与Aβ的C端结构域相互作用的apoE2和E3，而不是apoE4，可抑制非纤维状Aβ肽与神经元质膜的相互作用、Aβ肽聚集及随后的神经毒性。
