The formation of amyloid-β (Aβ) aggregates in brain is a neuropathological hallmark of Alzheimer’s disease (AD). However, there is mounting evidence that Aβ also plays a pathogenic role in other types of dementia and that specific post-translational Aβ modifications contribute to its pathogenic profile. The objective of this study was to test the hypothesis that distinct types of dementia are characterized by specific patterns of post-translationally modified Aβ variants. We conducted a comparative analysis and quantified Aβ as well as Aβ with pyroglutamate (pGlu3-Aβ and pGlu11-Aβ), N-truncation (Aβ(4-X)), isoaspartate racemization (isoAsp7-Aβ and isoAsp27-Aβ), phosphorylation (pSer8-Aβ and pSer26-Aβ) or nitration (3NTyr10-Aβ) modification in post mortem human brain tissue from non-demented control subjects in comparison to tissue classified as pre-symptomatic AD (Pre-AD), AD, dementia with Lewy bodies and vascular dementia. Aβ modification-specific immunohistochemical labelings of brain sections from the posterior superior temporal gyrus were examined by machine learning-based segmentation protocols and immunoassay analyses in brain tissue after sequential Aβ extraction were carried out. Our findings revealed that AD cases displayed the highest concentrations of all Aβ variants followed by dementia with Lewy bodies, Pre-AD, vascular dementia and non-demented controls. With both analytical methods, we identified the isoAsp7-Aβ variant as a highly abundant Aβ form in all clinical conditions, followed by Aβ(4-X), pGlu3-Aβ, pGlu11-Aβ and pSer8-Aβ. These Aβ variants were detected in distinct plaque types of compact, coarse-grained, cored and diffuse morphologies and, with varying frequencies, in cerebral blood vessels. The 3NTyr10-Aβ, pSer26-Aβ and isoAsp27-Aβ variants were not found to be present in Aβ plaques but were detected intraneuronally. There was a strong positive correlation between isoAsp7-Aβ and Thal phase and a moderate negative correlation between isoAsp7-Aβ and performance on the Mini Mental State Examination. Furthermore, the abundance of all Aβ variants was highest in APOE 3/4 carriers. In aggregation assays, the isoAsp7-Aβ, pGlu3-Aβ and pGlu11-Aβ variants showed instant fibril formation without lag phase, whereas Aβ(4-X), pSer26-Aβ and isoAsp27-Aβ did not form fibrils. We conclude that targeting Aβ post-translational modifications, and in particular the highly abundant isoAsp7-Aβ variant, might be considered for diagnostic and therapeutic approaches in different types of dementia. Hence, our findings might have implications for current antibody-based therapies of AD.

淀粉样蛋白β （Aβ） 聚集体在大脑中形成是阿尔茨海默病 （AD） 的神经病理学标志。然而，越来越多的证据表明 Aβ 在其他类型的痴呆中也起致病作用，并且特定的翻译后 Aβ 修饰有助于其致病特征。本研究的目的是检验以下假设：不同类型的痴呆以翻译后修饰的 Aβ 变体的特定模式为特征。我们进行了比较分析并量化了 Aβ 以及 Aβ 与焦谷氨酸（pGlu3-Aβ 和 pGlu11-Aβ）、N-截短 （Aβ（4-X））、异天冬氨酸外消旋化 （isoAsp7-Aβ 和 isoAsp27-Aβ）、磷酸化 （pSer8-Aβ 和 pSer26-Aβ） 或硝化 （3NTyr10-Aβ） 修饰在非痴呆对照受试者的死后人脑组织中与分类为症状前 AD （Pre-AD）、AD、路易体痴呆和血管性痴呆的组织相比。通过基于机器学习的分割方案检查颞上回后脑切片的 Aβ 修饰特异性免疫组织化学标记，并在连续 Aβ 提取后对脑组织进行免疫测定分析。我们的研究结果显示，AD 病例显示所有 Aβ 变体的浓度最高，其次是路易体痴呆、AD 前期、血管性痴呆和非痴呆对照。使用这两种分析方法，我们将 isoAsp7-Aβ 变体鉴定为在所有临床条件下都高度丰富的 Aβ 形式，其次是 Aβ （4-X） 、 pGlu3-Aβ 、 pGlu11-Aβ 和 pSer8-Aβ。这些 Aβ 变体在致密、粗粒、有芯和弥漫形态的不同斑块类型中检测到，并且在脑血管中以不同的频率检测到。 3NTyr10-Aβ 、 pSer26-Aβ 和 isoAsp27-Aβ 变体未发现存在于 Aβ 斑块中，但在神经元内检测到。isoAsp7-Aβ 与 Thal 期之间存在很强的正相关，isoAsp7-Aβ 与简易精神状态检查的表现呈中度负相关。此外，所有 Aβ 变体在 APOE 3/4 载体中的丰度最高。在聚集试验中，isoAsp7-Aβ、pGlu3-Aβ 和 pGlu11-Aβ 变体显示即时原纤维形成而没有滞后期，而 Aβ（4-X）、pSer26-Aβ 和 isoAsp27-Aβ 未形成原纤维。我们得出结论，靶向 Aβ 翻译后修饰，特别是高度丰富的 isoAsp7-Aβ 变体，可以考虑用于不同类型痴呆的诊断和治疗方法。因此，我们的研究结果可能对当前基于抗体的 AD 疗法产生影响。