The deposition of neurotoxic amyloid-β (Aβ) peptides in extracellular plaques in the brain parenchyma is one of the most prominent neuropathological features of Alzheimer’s disease (AD), and considered to be closely related to the pathogenesis of this disease. A number of recent studies demonstrate the heterogeneity in the composition of Aβ deposits in AD brains, due to the occurrence of elongated, truncated and post-translationally modified Aβ peptides that have peculiar characteristics in aggregation behavior and biostability. Importantly, the detection of modified Aβ species has been explored to characterize distinct stages of AD, with phosphorylated Aβ being present in the clinical phase of AD. People with Down syndrome (DS) develop AD pathology by 40 years of age likely due to the overproduction of Aβ caused by the additional copy of the gene encoding the amyloid precursor protein on chromosome 21. In the current study, we analysed the deposition of phosphorylated and non-phosphorylated Aβ species in human DS, AD, and control brains. In addition, deposition of these Aβ species was analysed in brains of a series of established transgenic AD mouse models using phosphorylation-state specific Aβ antibodies. Significant amounts of Aβ phosphorylated at serine residue 8 (pSer8Aβ) and unmodified Aβ were detected in the brains of DS and AD cases. The brains of different transgenic mouse models with either only human mutant amyloid precursor protein (APP), or combinations of human mutant APP, Presenilin (PS), and tau transgenes showed distinct age-dependent and spatiotemporal deposition of pSer8Aβ in extracellular plaques and within the vasculature. Together, these results demonstrate the deposition of phosphorylated Aβ species in DS brains, further supporting the similarity of Aβ deposition in AD and DS. Thus, the detection of phosphorylated and other modified Aβ species could contribute to the understanding and dissection of the complexity in the age-related and spatiotemporal deposition of Aβ variants in AD and DS as well as in distinct mouse models.

中文翻译：

---

人类唐氏综合症大脑和不同的阿尔茨海默氏症小鼠模型中的磷酸化Aβ肽。

神经毒性淀粉样蛋白（Aβ）肽在脑实质中的细胞外斑块中的沉积是阿尔茨海默病（AD）最突出的神经病理特征之一，并且被认为与该疾病的发病机理密切相关。大量最新研究表明，由于长形，截短和翻译后修饰的Aβ肽在聚集行为和生物稳定性方面具有独特的特征，导致AD脑中Aβ沉积物组成的异质性。重要的是，已经探索了检测修饰的Aβ种类以表征AD的不同阶段的特征，在AD的临床阶段中存在磷酸化的Aβ。患有唐氏综合症（DS）的人到40岁时发展为AD病理，这可能是由于21号染色体上编码淀粉样前体蛋白的基因的额外拷贝引起的Aβ过量产生所致。在本研究中，我们分析了磷酸化的沉积DS，AD和对照大脑中的非磷酸化Aβ物种。此外，使用磷酸化状态特异性Aβ抗体在一系列已建立的转基因AD小鼠模型的大脑中分析了这些Aβ种类的沉积。在DS和AD病例的脑中检测到大量的丝氨酸残基8（pSer8Aβ）磷酸化的Aβ和未修饰的Aβ。仅具有人类突变淀粉样前体蛋白（APP）或人类突变APP，早老素（PS）组合的不同转基因小鼠模型的大脑 tau和tau转基因在细胞外斑块和脉管系统中显示出明显的年龄依赖性和时空沉积pSer8Aβ。总之，这些结果证明了磷酸化的Aβ物质在DS脑中的沉积，进一步支持了AD和DS中Aβ沉积的相似性。因此，磷酸化和其他修饰的Aβ物种的检测可能有助于理解和解剖AD和DS以及不同小鼠模型中Aβ变体的年龄相关性和时空沉积的复杂性。