Puente-Bedia Alba, Berciano María T, Martínez-Cué Carmen, Lafarga Miguel, Rueda Noemí
Departamento de Fisiología y Farmacología, Facultad de Medicina, Universidad de Cantabria, 39011 Santander, Spain.
Departamento de Biología Molecular, "Red Sobre Enfermedades Neurodegenerativas (CIBERNED)", Universidad de Cantabria-IDIVAL, 39011 Santander, Spain.
Antioxidants (Basel). 2022 Dec 9;11(12):2438. doi: 10.3390/antiox11122438.
Oxidative stress (OS) is one of the neuropathological mechanisms responsible for the deficits in cognition and neuronal function in Down syndrome (DS). The Ts65Dn (TS) mouse replicates multiple DS phenotypes including hippocampal-dependent learning and memory deficits and similar brain oxidative status. To better understand the hippocampal oxidative profile in the adult TS mouse, we analyzed cellular OS-associated alterations in hippocampal granule cells (GCs), a neuronal population that plays an important role in memory formation and that is particularly affected in DS. For this purpose, we used biochemical, molecular, immunohistochemical, and electron microscopy techniques. Our results indicate that TS GCs show important OS-associated alterations in the systems essential for neuronal homeostasis: DNA damage response and proteostasis, particularly of the proteasome and lysosomal system. Specifically, TS GCs showed: (i) increased DNA damage, (ii) reorganization of nuclear proteolytic factories accompanied by a decline in proteasome activity and cytoplasmic aggregation of ubiquitinated proteins, (iii) formation of lysosomal-related structures containing lipid droplets of cytotoxic peroxidation products, and (iv) mitochondrial ultrastructural defects. These alterations could be implicated in enhanced cellular senescence, accelerated aging and neurodegeneration, and the early development of Alzheimer's disease neuropathology present in TS mice and the DS population.
氧化应激(OS)是导致唐氏综合征(DS)认知和神经元功能缺陷的神经病理机制之一。Ts65Dn(TS)小鼠复制了多种DS表型,包括海马依赖性学习和记忆缺陷以及类似的脑氧化状态。为了更好地了解成年TS小鼠的海马氧化特征,我们分析了海马颗粒细胞(GCs)中与细胞OS相关的改变,海马颗粒细胞是在记忆形成中起重要作用且在DS中特别易受影响的神经元群体。为此,我们使用了生化、分子、免疫组织化学和电子显微镜技术。我们的结果表明,TS GCs在神经元稳态所必需的系统中显示出与OS相关的重要改变:DNA损伤反应和蛋白质稳态,特别是蛋白酶体和溶酶体系统的蛋白质稳态。具体而言,TS GCs表现出:(i)DNA损伤增加,(ii)核蛋白水解工厂的重组,伴随着蛋白酶体活性下降和泛素化蛋白的细胞质聚集,(iii)含有细胞毒性过氧化产物脂滴的溶酶体相关结构的形成,以及(iv)线粒体超微结构缺陷。这些改变可能与细胞衰老增强、加速衰老和神经退行性变以及TS小鼠和DS人群中存在的阿尔茨海默病神经病理学的早期发展有关。