Li Qiao-Xin, Mok Su San, Laughton Katrina M, McLean Catriona A, Volitakis Irene, Cherny Robert A, Cheung Nam Sang, White Anthony R, Masters Colin L
Department of Pathology, The University of Melbourne, and The Mental Health Research Institute of Victoria, Parkville, Vic. 3010, Australia.
Aging Cell. 2006 Apr;5(2):153-65. doi: 10.1111/j.1474-9726.2006.00200.x.
Transgenic mice carrying mutant Cu/Zn superoxide dismutase (SOD1) recapitulate the motor impairment of human amyotrophic lateral sclerosis (ALS). The amyloid-beta (Abeta) peptide associated with Alzheimer's disease is neurotoxic. To investigate the potential role of Abeta in ALS development, we generated a double transgenic mouse line that overexpresses SOD1(G93A) and amyloid precursor protein (APP)-C100. The transgenic mouse C100.SOD1(G93A) overexpresses Abeta and shows earlier onset of motor impairment but has the same lifespan as the single transgenic SOD1(G93A) mouse. To determine the mechanism associated with this early-onset phenotype, we measured copper and zinc levels in brain and spinal cord and found both significantly elevated in the single and double transgenic mice compared with their littermate control mice. Increased glial fibrillary acidic protein and decreased APP levels in the spinal cord of C100.SOD1(G93A) mice compared with the SOD1(G93A) mice agree with the neuronal damage observed by immunohistochemical analysis. In the spinal cords of C100.SOD1(G93A) double transgenic mice, soluble Abeta was elevated in mice at end-stage disease compared with the pre-symptomatic stage. Buffer-insoluble SOD1 aggregates were significantly elevated in the pre-symptomatic mice of C100.SOD1(G93A) compared with the age-matched SOD1(G93A) mice, correlating with the earlier onset of motor impairment in the C100.SOD1(G93A) mice. This study supports abnormal SOD1 protein aggregation as the pathogenic mechanism in ALS, and implicates a potential role for Abeta in the development of ALS by exacerbating SOD1(G93A) aggregation.
携带突变型铜锌超氧化物歧化酶（SOD1）的转基因小鼠重现了人类肌萎缩侧索硬化症（ALS）的运动功能障碍。与阿尔茨海默病相关的β淀粉样蛋白（Aβ）具有神经毒性。为了研究Aβ在ALS发病过程中的潜在作用，我们构建了一种双转基因小鼠品系，该品系过表达SOD1（G93A）和淀粉样前体蛋白（APP）-C100。转基因小鼠C100.SOD1（G93A）过表达Aβ，且运动功能障碍发病更早，但寿命与单转基因SOD1（G93A）小鼠相同。为了确定与这种早发性表型相关的机制，我们测量了脑和脊髓中的铜和锌水平，发现与同窝对照小鼠相比，单转基因和双转基因小鼠中的铜和锌水平均显著升高。与SOD1（G93A）小鼠相比，C100.SOD1（G93A）小鼠脊髓中胶质纤维酸性蛋白增加而APP水平降低，这与免疫组织化学分析观察到的神经元损伤一致。在C100.SOD1（G93A）双转基因小鼠的脊髓中，与症状前期相比，终末期疾病小鼠的可溶性Aβ升高。与年龄匹配的SOD1（G93A）小鼠相比，C100.SOD1（G93A）症状前期小鼠中缓冲液不溶性SOD1聚集体显著升高，这与C100.SOD1（G93A）小鼠运动功能障碍发病更早相关。这项研究支持异常的SOD1蛋白聚集是ALS的致病机制，并暗示Aβ通过加剧SOD1（G93A）聚集在ALS发病过程中具有潜在作用。
