Background:The amyloid cascade hypothesis of Alzheimer’s disease (AD) posits that amyloid-β (Aβ) protein accumulation underlies the pathogenesis of the disease by leading to the formation of amyloid plaques, a pathologic hallmark of AD. Aβ is a proteolytic product of amyloid-β protein precursor (AβPP; APP), which is expressed in both neurons and astrocytes. Although considerable evidence shows that astrocytes may play critical roles in the pathogenesis of AD, the longitudinal changes of amyloid plaques in relationship to AβPP expression in astrocytes and cellular consequences are largely unknown. Objective:Here, we aimed to investigate astrocyte-related pathological changes of Aβ and AβPP using immunohistochemistry and biochemical studies in both animal and cell models. Methods/Results:Weutilized 5XFAD transgenic mice and found age-dependent upregulation of AβPP in astrocytes demonstrated with astrocytic reactive properties, which followed appearance of amyloid plaques in the brain. We also observed that AβPP proteins presented well-defined punctate immuno reactivity in young animals, whereas AβPP staining showed disrupted structures surrounding amyloid plaques in older mice. Moreover, we utilized astrocyte cell models and showed that pretreatment of Aβ42 resulted in downstream astrocyte autonomous changes, including up regulation in AβPP and BACE1 levels, as well as prolonged amyloidogenesis that could be reduced by pharmacological inhibition of BACE1. Conclusion:Collectively, our results show that age-dependent AβPP up regulation in astrocytes is a key feature in AD, which will not only provide novel insights for understanding AD progression, but also may offer new therapeutic strategies for treating AD.

中文翻译：

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星形胶质细胞体外和体内阿尔茨海默氏病淀粉样蛋白β前体的上调。

背景：阿尔茨海默氏病（AD）的淀粉样蛋白级联假设认为，β-淀粉样蛋白（Aβ）的蛋白积累通过导致淀粉样蛋白斑（AD的病理学特征）的形成而成为疾病发病机理的基础。Aβ是淀粉样β蛋白前体（AβPP; APP）的蛋白水解产物，在神经元和星形胶质细胞中均表达。尽管大量证据表明星形胶质细胞可能在AD的发病机制中发挥关键作用，但淀粉状蛋白斑块的纵向变化与星形胶质细胞中AβPP表达的关系以及细胞后果尚不明确。目的：在这里，我们旨在通过免疫组织化学和生化研究在动物和细胞模型中研究与星形胶质细胞相关的Aβ和AβPP病理变化。方法/结果：我们利用5XFAD转基因小鼠，发现星形胶质细胞中AβPP的年龄依赖性上调具有星形细胞反应特性，随后在大脑中出现淀粉样斑块。我们还观察到，AβPP蛋白在年幼动物中表现出良好的点状免疫反应性，而AβPP染色显示老年小鼠淀粉样蛋白斑块周围的结构受到破坏。此外，我们利用星形胶质细胞模型，表明Aβ42的预处理导致下游星形胶质细胞自主性变化，包括AβPP和BACE1水平的上调，以及淀粉样蛋白生成的延长，可以通过药理抑制BACE1来减少。结论：我们的研究结果表明，星形胶质细胞中年龄依赖性的AβPP上调是AD的关键特征，