Modified amyloid variants in pathological subgroups of b -amyloidosis

Objective : Amyloid b (A b ) depositions in plaques and cerebral amyloid angiopathy (CAA) represent common features of Alzheimer’s disease (AD). Sequential deposition of post-translationally modified A b in plaques character-izes distinct biochemical stages of A b maturation. However, the molecular composition of vascular A b deposits in CAA and its relation to plaques remain enigmatic. Methods : Vascular and parenchymal deposits were immunohisto-chemically analyzed for pyroglutaminated and phosphorylated A b in the medial temporal and occipital lobe of 24 controls, 27 pathologically-defined preclinical AD, and 20 symptomatic AD cases. Results : Sequential deposition of A b in CAA resembled A b maturation in plaques and enabled the distinction of three biochemical stages of CAA. B-CAA stage 1 was characterized by deposition of A b in the absence of pyroglutaminated A b N3pE and phosphorylated A b pS8 . B-CAA stage 2 showed additional A b N3pE and B-CAA stage 3 additional A b pS8 . Based on the A b maturation staging in CAA and plaques, three case groups for A b pathology could be distinguished: group 1 with advanced A b maturation in CAA; group 2 with equal A b maturation in CAA and plaques; group 3 with advanced A b maturation in plaques. All symptomatic AD cases presented with end-stage plaque maturation, whereas CAA could exhibit immature A b deposits. Notably, A b pathology group 1 was associated with arterial hypertension, and group 2 with the development of dementia. Interpretation : Balance of A b maturation in CAA and plaques defines distinct pathological

目的：斑块中的β淀粉样蛋白（Aβ）沉积和脑淀粉样血管病（CAA）是阿尔茨海默病（AD）的常见特征。翻译后修饰的Aβ在斑块中的顺序沉积表征了Aβ成熟的不同生化阶段。然而，CAA中血管Aβ沉积物的分子组成及其与斑块的关系仍然不清楚。 方法：对24例对照、27例病理定义的临床前AD和20例有症状的AD病例的内侧颞叶和枕叶中的血管和实质沉积物进行焦谷氨酸化和磷酸化Aβ的免疫组织化学分析。 结果：CAA中Aβ的顺序沉积类似于斑块中Aβ的成熟，并能够区分CAA的三个生化阶段。B - CAA 1期的特征是在没有焦谷氨酸化AβN3pE和磷酸化AβpS8的情况下Aβ沉积。B - CAA 2期显示有额外的AβN3pE，B - CAA 3期有额外的AβpS8。基于CAA和斑块中Aβ成熟的分期，可以区分出三个Aβ病理学病例组：第1组CAA中Aβ成熟晚期；第2组CAA和斑块中Aβ成熟程度相同；第3组斑块中Aβ成熟晚期。所有有症状的AD病例都呈现斑块成熟的终末期，而CAA可能表现出不成熟的Aβ沉积。值得注意的是，Aβ病理学第1组与动脉高血压相关，第2组与痴呆的发展相关。 解释：CAA和斑块中Aβ成熟的平衡定义了不同的病理状态。