Stereospecific interactions are necessary for Alzheimer disease amyloid-β toxicity
Stereospecific interactions are necessary for Alzheimer disease amyloid-β toxicity
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DOI：
10.1016/j.neurobiolaging.2009.02.018
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发表时间：
2011-02-01
影响因子：
4.2
通讯作者：
Cappai, Roberto
中科院分区：
文献类型：
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作者：
Ciccotosto, Giuseppe D.;Tew, Deborah J.;Cappai, Roberto
先前的研究表明，膜结合是淀粉样β蛋白(Aβ)神经毒性的关键决定因素。然而，目前还不清楚这种相互作用是否由受体驱动。为了解决这一问题，合成了Aβ42的D-手性对映体(D-Aβ42)，并将其生物物理和神经毒性性质与野生型Aβ42(L-Aβ42)进行了比较。结果表明，D-和L-Aβ42在铜结合、产生活性氧物种和聚集态等方面具有化学等效性。细胞结合研究表明，这两种多肽都能与培养的大脑皮层神经元结合。然而，只有L-Aβ42具有神经毒性和抑制长时程增强作用，这表明L-Aβ42需要一个立体特异的靶点来介导毒性。我们鉴定了磷脂酰丝氨酸，作为一个潜在的靶点。与外化磷脂酰丝氨酸有很高亲和力的Annexin V显著抑制L-Aβ42与培养的皮质神经元的结合，但不抑制D-Aβ42与培养的皮质神经元的结合，并显著挽救L-Aβ42的神经毒性。这表明阿尔茨海默病的所有中介毒性都依赖于神经细胞上磷脂酰丝氨酸的所有结合。(C)2009 Elsevier Inc.保留所有权利。
Previous studies suggest membrane binding is a key determinant of amyloid beta (A beta) neurotoxicity. However, it is unclear whether this interaction is receptor driven. To address this issue, a D-handed enantiomer of A beta 42 (D-A beta 42) was synthesized and its biophysical and neurotoxic properties were compared to the wild-type A beta 42 (L-A beta 42). The results showed D- and L-A beta 42 are chemically equivalent with respect to copper binding, generation of reactive oxygen species and aggregation profiles. Cell binding studies show both peptides bound to cultured cortical neurons. However, only L-A beta 42 was neurotoxic and inhibited long term potentiation indicating L-A beta 42 requires a stereospecific target to mediate toxicity. We identified the lipid phosphatidylserine, as a potential target. Annexin V, which has very high affinity for externalized phosphatidylserine, significantly inhibited L-A beta 42 but not D-A beta 42 binding to the cultured cortical neurons and significantly rescued L-A beta 42 neurotoxicity. This suggests that All mediated toxicity in Alzheimer disease is dependent upon All binding to phosphatidylserine on neuronal cells. (C) 2009 Elsevier Inc. All rights reserved.