Necroptosis is a regulated form of cell death that has been observed in Alzheimer’s disease (AD) along with the classical pathological hallmark lesions of amyloid plaques and Tau neurofibrillary tangles. To understand the neurodegenerative process in AD, we studied the role of necroptosis in mouse models and primary mouse neurons. Using immunohistochemistry, we demonstrated activated necroptosis-related proteins in transgenic mice developing Tau pathology and in primary neurons from amyloid precursor protein (APP)–Tau double transgenic mice treated with phosphorylated Tau seeds derived from a patient with AD but not in APP transgenic mice that only exhibited β-amyloid deposits. Necroptosis proteins in granulovacuolar degeneration (GVD) bodies were associated with neuronal loss in mouse brain regions also known to be vulnerable to GVD in the human AD brain. Necroptosis inhibitors lowered the percentage of neurons showing GVD and reduced neuronal loss, both in transgenic mice and in primary mouse neurons. This suggests that a GVD-associated form of necroptosis that we refer to as “GVD-necroptosis” may represent a delayed form of necroptosis in AD. We propose that inhibition of necroptosis could rescue this type of neuronal death in AD.

中文翻译：

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抑制阿尔茨海默病相关的坏死性凋亡，在小鼠模型中挽救神经元死亡


坏死性凋亡是一种受调节的细胞死亡形式，已在阿尔茨海默病 （AD） 中观察到，同时还观察到淀粉样蛋白斑块和 Tau 神经原纤维缠结的经典病理标志病变。为了了解 AD 中的神经退行性过程，我们研究了坏死性凋亡在小鼠模型和原代小鼠神经元中的作用。使用免疫组织化学，我们在发生 Tau 病理学的转基因小鼠和淀粉样蛋白前体蛋白 （APP）-Tau 双转基因小鼠的原代神经元中证明了激活的坏死性凋亡相关蛋白，这些小鼠用来自 AD 患者的磷酸化 Tau 种子处理，但在仅表现出 β-淀粉样蛋白沉积物的 APP 转基因小鼠中没有。粒细胞增多变性 （GVD） 体内的坏死性凋亡蛋白与小鼠大脑区域的神经元丢失有关，该区域也已知在人 AD 大脑中易受 GVD 的影响。坏死性凋亡抑制剂降低了转基因小鼠和原代小鼠神经元中显示 GVD 的神经元百分比并减少了神经元丢失。这表明，我们称之为“GVD 坏死性凋亡”的 GVD 相关坏死性凋亡可能代表 AD 中迟发性坏死性凋亡。我们提出抑制坏死性凋亡可以挽救 AD 中的这种类型的神经元死亡。