A synthetic peptide blocking the apolipoprotein E/β-amyloid binding mitigates β-amyloid toxicity and fibril formation in vitro and reduces β-amyloid plaques in transgenic mice
A synthetic peptide blocking the apolipoprotein E/β-amyloid binding mitigates β-amyloid toxicity and fibril formation in vitro and reduces β-amyloid plaques in transgenic mice
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DOI：
10.1016/s0002-9440(10)63355-x
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发表时间：
2004-09-01
影响因子：
6
通讯作者：
Wisniewski, T
中科院分区：
文献类型：
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作者：
Sadowski, M;Pankiewicz, J;Wisniewski, T
阿尔茨海默病（AD）与β-淀粉样蛋白（Abeta）的积累有关。散发性AD的一个主要遗传危险因素是载脂蛋白（apo）E4等位基因的遗传。ApoE可以作为Abeta的病理性伴侣，促进其从可溶性Abeta到毒性聚集体的构象转化。我们确定阻断apoE/Abeta相互作用是否会降低转基因（Tg）AD小鼠中的Abeta负荷。ApoE在Abeta上的结合位点对应于残基12至28。为了阻断结合，我们合成了含有这些残基的肽，但将18位的缬氨酸取代为脯氨酸（Abeta12 - 28P）。这改变了肽的性质，使其非纤维化和无毒。A β 12 - 28 P竞争性阻断全长A β 6与apoE的结合（IC 50 = 36.7 nmol）。此外，Abeta 12 - 28 P在apoE存在下减少Abeta原纤维形成，并减少细胞培养物中的Abeta/apoE毒性。Abeta12 - 28 P是血脑屏障可渗透的，并且在AD Tg小鼠中抑制Abeta沉积。与年龄匹配的对照Tg小鼠相比，用Abeta12 - 28P治疗1个月的Tg小鼠皮质中Abeta负荷减少63.3%（P = 0.0043），海马中Abeta负荷减少59.5%（P = 0.0087）。在处理小鼠的血清中未检测到抗Abeta的抗体;因此，观察到的Abeta 12 - 28 P的治疗作用不能归因于抗体清除反应。我们的实验表明，阻断Abeta与其病理性chapcrones之间的相互作用的化合物可能有利于治疗AD中的β-淀粉样蛋白沉积。
Alzheimer's disease (AD) is associated with accumulation of beta-amyloid (Abeta). A major genetic risk factor for sporadic AD is inheritance of the apolipoprotein (apo) E4 allele. ApoE can act as a pathological chaperone of Abeta, promoting its conformational transformation from soluble Abeta into toxic aggregates. We determined if blocking the apoE/Abeta interaction reduces Abeta load in transgenic (Tg) AD mice. The binding site of apoE on Abeta corresponds to residues 12 to 28. To block binding, we synthesized a peptide containing these residues, but substituted valine at position 18 to proline (Abeta12-28P). This changed the peptide's properties, making it non-fibrillogenic and non-toxic. Abeta12-28P competitively blocks binding of full-length A,6 to apoE (IC50 = 36.7 nmol). Furthermore, Abeta12-28P reduces Abeta fibrillogenesis in the presence of apoE, and Abeta/apoE toxicity in cell culture. Abeta12-28P is blood-brain barrier-permeable and in AD Tg mice inhibits Abeta deposition. Tg mice treated with Abeta12-28P for 1 month had a 63.3% reduction in Abeta load in the cortex (P = 0.0043) and a 59.5% (P = 0.0087) reduction in the hippocampus comparing to age-matched control Tg mice. Antibodies against Abeta were not detected in sera of treated mice; therefore the observed therapeutic effect of Abeta12-28P cannot be attributed to an antibody clearance response. Our experiments demonstrate that compounds blocking the interaction between Abeta and its pathological chapcrones may be beneficial for treatment of beta-amyloid deposition in AD.