The mechanism governing senile plaque generation in Alzheimer's disease (AD) remains intensively debated. We analyzed AD brain tissues with histochemistry, immunohistochemistry and fluorescence imaging. We found little co-expression between neural markers and plaque Aβ while abundant co-expression between blood or plasma markers such as HBA, HbA1C, Hemin, ApoE and plaque Aβ. The cores of dense-core plaques were structured with vascular proteins and glial processes at the periphery and blood metabolites in the center. Senile plaques additionally co-localized with a characteristic Hoechst-staining-independent blue autofluorescence, likely also derived from red blood cells. Aβ interacts with hemoglobin in an in vitro assay and also at single cell levels in red blood cells in vivo, showing as dots, stripes or diffusive patterns with its intensity correlated with coagulation, the elevation of calcium and blue autofluorescence. Interaction between Aβ and ApoE in the blood stream forms vascular amyloid plaques that restrict red blood cell passage. The interaction of Aβ and red blood cells associates with multiple blood and vascular defects besides CAA, including increased perivascular space, microaneurysm, intravascular hemolysis and vascular calcification. Senile plaque formation was intrinsically linked to vascular degeneration as shown by LRP1, ColIV and ACTA2 immunostaining. Aβ staining also overlapped with Cathepsin D expression in intravascular hemolysis, CAA， microaneurysm and senile plaques in AD brain tissues. Microaneurysms with chronic hemolysis were identified as important sites of amyloid formation besides CAA and intravascular hemolysis. In summary, our data suggested that senile plaques arise from Aβ and Cathepsin D-enriched amyloid mixtures out of intravascular hemolysis and Charcot-Bouchard aneurysm-related vascular degeneration. In addition, hemoglobin could be a primary physiological target of Aβ.

中文翻译：

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阿尔茨海默病中的老年斑来源于血管内溶血和 Charcot-Bouchard 动脉瘤相关血管变性中富含 Aβ 和组织蛋白酶 D 的淀粉样蛋白混合物

阿尔茨海默病 (AD) 中控制老年斑生成的机制仍存在激烈争论。我们用组织化学、免疫组织化学和荧光成像分析了 AD 脑组织。我们发现神经标志物和斑块 Aβ 之间几乎没有共表达，而血液或血浆标志物如 HBA、HbA1C、血红素、ApoE 和斑块 Aβ 之间有大量共表达。致密斑块的核心由外围的血管蛋白和神经胶质突起和中心的血液代谢物构成。老年斑还与特征性的不依赖赫斯特染色的蓝色自发荧光共同定位，可能也来自红细胞。Aβ 在体外测定中与血红蛋白相互作用，在体内红细胞中也与单细胞水平相互作用，显示为点，条纹或漫射图案，其强度与凝血、钙的升高和蓝色自发荧光有关。血流中 Aβ 和 ApoE 之间的相互作用形成限制红细胞通过的血管淀粉样蛋白斑块。除了 CAA 外，Aβ 和红细胞的相互作用与多种血液和血管缺陷有关，包括血管周围空间增加、微动脉瘤、血管内溶血和血管钙化。如 LRP1、ColIV 和 ACTA2 免疫染色所示，老年斑形成与血管变性存在内在联系。Aβ染色也与AD脑组织血管内溶血、CAA、微动脉瘤和老年斑中组织蛋白酶D的表达重叠。除 CAA 和血管内溶血外，伴有慢性溶血的微动脉瘤被认为是淀粉样蛋白形成的重要部位。总之，我们的数据表明，老年斑是由血管内溶血和 Charcot-Bouchard 动脉瘤相关血管变性引起的富含 Aβ 和组织蛋白酶 D 的淀粉样蛋白混合物产生的。此外，血红蛋白可能是 Aβ 的主要生理目标。