Department of Neurology, University of California at Los Angeles, 90025, USA.
Biochem J. 2011 Jan 15;433(2):323-32. doi: 10.1042/BJ20101391.
Aβ (amyloid β-peptide) is believed to cause AD (Alzheimer's disease). Aβ42 (Aβ comprising 42 amino acids) is substantially more neurotoxic than Aβ40 (Aβ comprising 40 amino acids), and this increased toxicity correlates with the existence of unique Aβ42 oligomers. Met³⁵ oxidation to sulfoxide or sulfone eliminates the differences in early oligomerization between Aβ40 and Aβ42. Met³⁵ oxidation to sulfoxide has been reported to decrease Aβ assembly kinetics and neurotoxicity, whereas oxidation to sulfone has rarely been studied. Based on these data, we expected that oxidation of Aβ to sulfone would also decrease its toxicity and assembly kinetics. To test this hypothesis, we compared systematically the effect of the wild-type, sulfoxide and sulfone forms of Aβ40 and Aβ42 on neuronal viability, dendritic spine morphology and macroscopic Ca²(+) currents in primary neurons, and correlated the data with assembly kinetics. Surprisingly, we found that, in contrast with Aβ-sulfoxide, Aβ-sulfone was as toxic and aggregated as fast, as wild-type Aβ. Thus, although Aβ-sulfone is similar to Aβ-sulfoxide in its dipole moment and oligomer size distribution, it behaves similarly to wild-type Aβ in its aggregation kinetics and neurotoxicity. These surprising data decouple the toxicity of oxidized Aβ from its initial oligomerization, and suggest that our current understanding of the effect of methionine oxidation in Aβ is limited.
β 淀粉样蛋白（Aβ）被认为是导致 AD（阿尔茨海默病）的原因。Aβ42（由 42 个氨基酸组成的 Aβ）比 Aβ40（由 40 个氨基酸组成的 Aβ）具有更高的神经毒性，这种增加的毒性与独特的 Aβ42 低聚物的存在相关。Met³⁵ 氧化为亚砜或砜消除了 Aβ40 和 Aβ42 早期寡聚化之间的差异。据报道，Met³⁵ 氧化为亚砜会降低 Aβ 的组装动力学和神经毒性，而氧化为砜的情况很少被研究。基于这些数据，我们预计 Aβ 氧化为砜也会降低其毒性和组装动力学。为了验证这一假设，我们系统比较了野生型、亚砜和砜形式的 Aβ40 和 Aβ42 对原代神经元活力、树突棘形态和宏观 Ca²⁺电流的影响，并将数据与组装动力学相关联。令人惊讶的是，我们发现，与 Aβ-亚砜相反，Aβ-砜与野生型 Aβ一样具有毒性和快速聚集。因此，尽管 Aβ-砜在偶极矩和低聚物尺寸分布上与 Aβ-亚砜相似，但在聚集动力学和神经毒性方面与野生型 Aβ 相似。这些令人惊讶的数据将氧化 Aβ 的毒性与其初始寡聚化分离，并表明我们目前对甲硫氨酸氧化在 Aβ 中的作用的理解是有限的。
