抑制阿尔茨海默氏症相关的坏死形式可挽救小鼠模型中的神经元死亡。

IF 15.8 1区 医学 Q1 CELL BIOLOGY
Marta J. Koper, Sebastiaan Moonen, Alicja Ronisz, Simona Ospitalieri, Zsuzsanna Callaerts-Vegh, Dries T’Syen, Sabine Rabe, Matthias Staufenbiel, Bart De Strooper, Sriram Balusu, Dietmar Rudolf Thal
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引用次数: 0

摘要

坏死是细胞死亡的一种调节形式,在阿尔茨海默病(AD)中,除了淀粉样蛋白斑块和 Tau 神经纤维缠结等经典病理标志性病变外,还可观察到坏死。为了了解阿尔茨海默病的神经退行性过程,我们研究了坏死细胞在小鼠模型和原代小鼠神经元中的作用。利用免疫组化技术,我们在出现 Tau 病理变化的转基因小鼠体内以及淀粉样前体蛋白(APP)-Tau 双转基因小鼠的原代神经元中发现了活化的坏死相关蛋白,而在只表现出 β 淀粉样蛋白沉积的 APP 转基因小鼠体内则没有发现。颗粒细胞变性(GVD)体中的坏死蛋白与小鼠脑区的神经元损失有关,而已知人类AD脑区也容易发生GVD。在转基因小鼠和原代小鼠神经元中,坏死抑制剂降低了出现GVD的神经元比例,减少了神经元丢失。这表明,GVD 相关的坏死形式(我们称之为 "GVD-坏死")可能代表了 AD 中坏死的延迟形式。我们建议,抑制坏死凋亡可以挽救这种类型的 AD 神经元死亡。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Inhibition of an Alzheimer’s disease–associated form of necroptosis rescues neuronal death in mouse models
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.
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来源期刊
Science Translational Medicine
Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL
CiteScore
26.70
自引率
1.20%
发文量
309
审稿时长
1.7 months
期刊介绍: Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.
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