Amyloid plaques composed of fibrils of misfolded Aβ peptides are pathological hallmarks of Alzheimer’s disease (AD). Aβ fibrils are polymorphic in their tertiary and quaternary molecular structures. This structural polymorphism may carry different pathologic potencies and can putatively contribute to clinical phenotypes of AD. Therefore, mapping of structural polymorphism of Aβ fibrils and structural evolution over time is valuable to understanding disease mechanisms. Here, we investigated how Aβ fibril structures in situ differ in Aβ plaque of different mouse models expressing familial mutations in the AβPP gene. We imaged frozen brains with a combination of conformation-sensitive luminescent conjugated oligothiophene (LCO) ligands and Aβ-specific antibodies. LCO fluorescence mapping revealed that mouse models APP23, APPPS1, and App^NL-F have different fibril structures within Aβ-amyloid plaques depending on the AβPP-processing genotype. Co-staining with Aβ-specific antibodies showed that individual plaques from APP23 mice expressing AβPP Swedish mutation have two distinct fibril polymorph regions of core and corona. The plaque core is predominantly composed of compact Aβ40 fibrils, and the corona region is dominated by diffusely packed Aβ40 fibrils. Conversely, the AβPP knock-in mouse App^NL-F, expressing the AβPP Iberian mutation along with Swedish mutation has tiny, cored plaques consisting mainly of compact Aβ42 fibrils, vastly different from APP23 even at elevated age up to 21 months. Age-dependent polymorph rearrangement of plaque cores observed for APP23 and APPPS1 mice >12 months, appears strongly promoted by Aβ40 and was hence minuscule in App^NL-F. These structural studies of amyloid plaques in situ can map disease-relevant fibril polymorph distributions to guide the design of diagnostic and therapeutic molecules.

中文翻译：

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APP23、APPPS1 和 AppNL-F 小鼠 Aβ 淀粉样蛋白沉积物中不同年龄依赖性构象重排


由错误折叠的 Aβ 肽原纤维组成的淀粉样斑块是阿尔茨海默病 (AD) 的病理标志。 Aβ 原纤维的三级和四级分子结构具有多态性。这种结构多态性可能具有不同的病理效力，并且可能导致 AD 的临床表型。因此，绘制 Aβ 原纤维的结构多态性和随时间的结构演化对于理解疾病机制很有价值。在这里，我们研究了表达 AβPP 基因家族突变的不同小鼠模型的 Aβ 斑块中 Aβ 原纤维结构的原位差异。我们结合构象敏感的发光共轭低聚噻吩 (LCO) 配体和 Aβ 特异性抗体对冷冻大脑进行成像。 LCO 荧光图谱显示，小鼠模型 APP23、APPPS1 和 App ^NL-F 在 Aβ-淀粉样斑块内具有不同的原纤维结构，具体取决于 AβPP 加工基因型。与 Aβ 特异性抗体共染色显示，表达 AβPP瑞典突变的 APP23 小鼠的单个斑块具有两个不同的原纤维多态性区域：核心和冠状。斑块核心主要由致密的 Aβ40 原纤维组成，冠区主要由弥散堆积的 Aβ40 原纤维组成。相反，表达 AβPP 伊比利亚突变和瑞典突变的 AβPP 敲入小鼠 App ^NL-F 具有微小的核心斑块，主要由紧凑的 Aβ42 原纤维组成，即使在高达 21 个月的高龄时，也与 APP23 有很大不同。在 12 个月以上的 APP23 和 APPPS1 小鼠中观察到斑块核心的年龄依赖性多晶型重排，似乎受到 Aβ40 的强烈促进，因此在 App ^NL-F 中微不足道。 这些原位淀粉样斑块的结构研究可以绘制与疾病相关的原纤维多晶型分布图，以指导诊断和治疗分子的设计。