Laboratory for Neuropathology, Department of Imaging and Pathology, KU Leuven, Leuven Brain Institute (LBI), Leuven, Belgium.
Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, KU Leuven, Leuven Brain Institute (LBI), Leuven, Belgium.
Sci Transl Med. 2024 Oct 30;16(771):eadf5128. doi: 10.1126/scitranslmed.adf5128.
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.
细胞坏死是一种受调控的细胞死亡形式，在阿尔茨海默病（AD）中与淀粉样斑块和 Tau 神经原纤维缠结的经典病理特征病变一起被观察到。为了了解 AD 中的神经退行性过程，我们研究了细胞坏死在小鼠模型和原代小鼠神经元中的作用。通过免疫组织化学，我们在发生 Tau 病理的转基因小鼠和用源自 AD 患者的磷酸化 Tau 种子处理的淀粉样前体蛋白（APP）-Tau 双转基因小鼠的原代神经元中证明了激活的与坏死相关的蛋白，但在仅表现出 β-淀粉样沉积的 APP 转基因小鼠中则没有。在已知在人类 AD 大脑中也易发生颗粒空泡变性（GVD）的小鼠脑区中，与 GVD 相关的坏死蛋白与神经元丢失有关。坏死抑制剂降低了显示 GVD 和减少神经元丢失的神经元百分比，无论是在转基因小鼠还是原代小鼠神经元中。这表明我们称之为“GVD-坏死”的与 GVD 相关的坏死形式可能代表 AD 中延迟的坏死形式。我们提出抑制坏死可能会挽救 AD 中的这种神经元死亡。
