Upregulation of Alzheimer's Disease Amyloid-β Protein Precursor in Astrocytes Both in vitro and in vivo.
Upregulation of Alzheimer's Disease Amyloid-β Protein Precursor in Astrocytes Both in vitro and in vivo.
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DOI：
10.3233/jad-200128
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Zhang C
中科院分区：
文献类型：
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作者：
Liang Y;Raven F;Ward JF;Zhen S;Zhang S;Sun H;Miller SJ;Choi SH;Tanzi RE;Zhang C
阿尔茨海默病 (AD) 的淀粉样蛋白级联假说认为，β 淀粉样蛋白 (Aβ) 蛋白的积累导致形成 β-淀粉样斑块（AD 的病理标志），从而成为该疾病发病机制的基础。 Aβ是β-淀粉样蛋白前体（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 β-淀粉样蛋白斑块的纵向变化与星形胶质细胞中 APP 表达的关系以及细胞后果在很大程度上尚不清楚。在这里，我们的目的是在动物和细胞模型中使用免疫组织化学和生化研究来研究星形胶质细胞相关的 β-淀粉样蛋白和 APP 的病理变化。我们利用 5XFAD 转基因小鼠，发现星形胶质细胞中 APP 呈年龄依赖性上调，并具有星形胶质细胞反应特性，这是随着大脑中淀粉样蛋白斑块的出现而出现的。我们还观察到，APP 蛋白在年轻动物中表现出明确的点状免疫反应性，而在年老小鼠中，淀粉样蛋白斑周围的结构则显示出破坏。此外，我们利用星形胶质细胞模型表明，Aβ42 预处理会导致下游星形胶质细胞自主变化，包括 APP 和 BACE1 水平上调，以及延长淀粉样蛋白生成，而淀粉样蛋白生成可通过药物抑制 BACE1 来减少。总的来说，我们的结果表明，星形胶质细胞中年龄依赖性 APP 上调是 AD 的一个关键特征，这不仅将为理解 AD 进展提供新的见解，而且可能为治疗 AD 提供新的治疗策略。
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 formation of β-amyloid plaques, a pathologic hallmark of AD. Aβ is a proteolytic product of β-amyloid 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 β-amyloid plaques in relationship to APP expression in astrocytes and cellular consequences are largely unknown. Here, we aimed to investigate astrocyte-related pathologic changes of β-amyloid and APP using immunohistochemistry and biochemical studies in both animal and cell models. We utilized 5XFAD transgenic mice and found age-dependent upregulation of APP in astrocytes demonstrated with astrocytic reactive properties, which followed appearance of amyloid plaques in the brain. We also observed that APP proteins presented well-defined punctate immunoreactivity in young animals that in contrast showed disrupted structures surrounding amyloid plaques in older mice. Moreover, we utilized astrocyte cell models and showed that pretreatment of Aβ42 resulted in down-stream astrocyte autonomous changes, including upregulation in APP and BACE1 levels, as well as prolonged amyloidogenesis that can be reduced by pharmacological inhibition of BACE1. Collectively, our results showed that age-dependent APP 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.