Department of Neurology, University of Bonn, 53127, Bonn, Germany.
Acta Neuropathol. 2013 May;125(5):699-709. doi: 10.1007/s00401-013-1107-8. Epub 2013 Mar 24.
The progressive accumulation of extracellular amyloid plaques in the brain is a common hallmark of Alzheimer's disease (AD). We recently identified a novel species of Aβ phosphorylated at serine residue 8 with increased propensity to form toxic aggregates as compared to non-phosphorylated species. The age-dependent analysis of Aβ depositions using novel monoclonal phosphorylation-state specific antibodies revealed that phosphorylated Aβ variants accumulate first inside of neurons in a mouse model of AD already at 2 month of age. At higher ages, phosphorylated Aβ is also abundantly detected in extracellular plaques. Besides a large overlap in the spatiotemporal deposition of phosphorylated and non-phosphorylated Aβ species, fractionized extraction of Aβ from brains revealed an increased accumulation of phosphorylated Aβ in oligomeric assemblies as compared to non-phosphorylated Aβ in vivo. Thus, phosphorylated Aβ could represent an important species in the formation and stabilization of neurotoxic aggregates, and might be targeted for AD therapy and diagnosis.
脑内细胞外淀粉样斑块的逐渐积累是阿尔茨海默病（AD）的一个常见标志。我们最近发现了一种新型的 Aβ，其在丝氨酸残基 8 处发生磷酸化，与非磷酸化的 Aβ相比，更倾向于形成有毒的聚集物。使用新型的单克隆磷酸化状态特异性抗体对 Aβ 沉积进行的年龄依赖性分析表明，在 AD 小鼠模型中，磷酸化的 Aβ 变体已经在 2 个月大时首先在神经元内积累。在更高的年龄，磷酸化的 Aβ 也在细胞外斑块中大量检测到。除了磷酸化和非磷酸化的 Aβ 物种在时空沉积上有很大的重叠之外，从大脑中分离的 Aβ 的分馏提取表明，与体内的非磷酸化的 Aβ 相比，磷酸化的 Aβ 在寡聚体组装中积累增加。因此，磷酸化的 Aβ 可能代表形成和稳定神经毒性聚集物的重要物质，并且可能成为 AD 治疗和诊断的靶点。
