Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Hum Mol Genet. 2012 Sep 1;21(17):3871-82. doi: 10.1093/hmg/dds215. Epub 2012 Jun 7.
In amyotrophic lateral sclerosis (ALS), the progressive loss of motor neurons is accompanied by extensive muscle denervation, resulting in paralysis and ultimately death. Upregulation of amyloid beta (A4) precursor protein (APP) in muscle fibres coincides with symptom onset in both sporadic ALS patients and the SOD1(G93A) mouse model of familial ALS. We have further characterized this response in SOD1(G93A) mice and also revealed elevated levels of β-amyloid (Aβ) peptides in the SOD1(G93A) spinal cord, which were predominantly localized within motor neurons and their surrounding glial cells. We therefore examined the effect of genetic ablation of APP on disease progression in SOD1(G93A) mice, which significantly improved multiple disease parameters, including innervation, motor function, muscle contractile characteristics, motor unit and motor neuron survival. These results therefore strongly suggest that APP actively contributes to SOD1(G93A)-mediated pathology. Together with observations from ALS cases, this study indicates that APP may contribute to human ALS pathology.
在肌萎缩侧索硬化症（ALS）中，运动神经元的进行性丧失伴随着广泛的肌肉去神经支配，导致瘫痪，最终导致死亡。淀粉样蛋白β（A4）前体蛋白（APP）在肌肉纤维中的上调与散发性 ALS 患者和家族性 ALS 的 SOD1（G93A）小鼠模型的症状发作同时发生。我们进一步对 SOD1（G93A）小鼠的这种反应进行了表征，还发现 SOD1（G93A）脊髓中的β-淀粉样蛋白（Aβ）肽水平升高，主要定位于运动神经元及其周围的神经胶质细胞内。因此，我们研究了 APP 基因缺失对 SOD1（G93A）小鼠疾病进展的影响，结果发现这显著改善了多种疾病参数，包括神经支配、运动功能、肌肉收缩特性、运动单位和运动神经元的存活。这些结果强烈表明 APP 积极参与了 SOD1（G93A）介导的病理过程。结合 ALS 病例的观察结果，本研究表明 APP 可能导致人类 ALS 病理学的发生。
