Alzheimer's disease (AD) is characterized by a specific pattern of neuropathological changes, including extracellular amyloid β (Aβ) deposits, intracellular neurofibrillary tangles (NFTs), granulovacuolar degeneration (GVD) representing cytoplasmic vacuolar lesions, synapse dysfunction and neuronal loss. Necroptosis, a programmed form of necrosis characterized by the assembly of the necrosome complex composed of phosphorylated proteins, i.e. receptor-interacting serine/threonine-protein kinase 1 and 3 (pRIPK1 and pRIPK3) and mixed lineage kinase domain-like protein (pMLKL), has recently been shown to be involved in AD. However, it is not yet clear whether necrosome assembly takes place in brain regions showing AD-related neuronal loss and whether it is associated with AD-related neuropathological changes. Here, we analyzed brains of AD, pathologically defined preclinical AD (p-preAD) and non-AD control cases to determine the neuropathological characteristics and distribution pattern of the necrosome components. We demonstrated that all three activated necrosome components can be detected in GVD lesions (GVDn+, i.e. GVD with activated necrosome) in neurons, that they colocalize with classical GVD markers, such as pTDP-43 and CK1δ, and similarly to these markers detect GVD lesions. GVDn + neurons inversely correlated with neuronal density in the early affected CA1 region of the hippocampus and in the late affected frontal cortex layer III. Additionally, AD-related GVD lesions were associated with AD-defining parameters, showing the strongest correlation and partial colocalization with NFT pathology. Therefore, we conclude that the presence of the necrosome in GVD plays a role in AD, possibly by representing an AD-specific form of necroptosis-related neuron death. Hence, necroptosis-related neuron loss could be an interesting therapeutic target for treating AD.

中文翻译：

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颗粒-肺泡变性中检测到的坏死复合物与阿尔茨海默氏病的神经元丢失有关。

阿尔茨海默氏病（AD）的特征在于神经病理学改变的特定模式，包括细胞外淀粉样β（Aβ）沉积物，细胞内神经原纤维缠结（NFT），代表细胞质液泡病变，颗粒突触功能障碍和神经元丢失的颗粒性小泡变性（GVD）。坏死性坏死，一种程序化的坏死形式，其特征在于坏死复合体的组装由磷酸化蛋白组成，即与受体相互作用的丝氨酸/苏氨酸蛋白激酶1和3（pRIPK1和pRIPK3）和混合谱系激酶结构域样蛋白（pMLKL）组成，最近被证明与AD有关。然而，尚不清楚是否坏死组装发生在显示与AD有关的神经元丧失的脑区域中，以及它是否与与AD有关的神经病理学改变有关。在这里，我们分析了AD的大脑，病理定义的临床前AD（p-preAD）和非AD对照病例，以确定坏死组分的神经病理学特征和分布方式。我们证明了可以在神经元的GVD病变（GVDn +，即具有激活的坏死体的GVD）中检测到所有三种激活的坏死成分，它们与经典GVD标记（例如pTDP-43和CK1δ）共定位，并且类似于这些标记来检测GVD病变。在早期受影响的海马CA1区和晚期受影响的额叶皮层III中，GVDn +神经元与神经元密度呈负相关。此外，AD相关的GVD病变与AD定义参数相关，显示出与NFT病理学最强的相关性和部分共定位。所以，我们得出的结论是，GVD中坏死体的存在可能在AD中发挥作用，可能是通过代表坏死病相关神经元死亡的AD特异性形式。因此，坏死病相关的神经元丢失可能是治疗AD的有趣治疗靶点。