Time-lines of neural degeneration in ALS-PDC mouse model

肌萎缩侧索硬化症-痴呆症复合体(ALS-PDC)是一种典型的神经系统疾病 肌萎缩侧索硬化症，一种类似阿尔茨海默氏症的疾病，具有相关的帕金森症特征，或两者的组合。它是一个星系团 年龄依赖性神经退行性疾病，这是唯一被广泛承认的此类疾病 并可能为相关疾病的病因学提供重要线索。我们已经成功地建立了这种疾病的模型 给成年小鼠喂食洗净的苏铁粉，会导致行为和组织病理学缺陷 类似肌萎缩侧索硬化症-前列腺癌。对疾病进行建模的能力使我们能够提出重大的基本问题 对相关疾病的潜在影响：环境毒素和遗传易感性与哪些因素有关 神经退行性变？从最初的世博会开始，行为和病理缺陷的时间进程是什么？ 确定直到行为结束状态吗？年龄如何影响疾病的发展和进展？最后，基于 在上述情况下，我们是否可以设计预防和早期治疗策略，以防止进一步的神经症- 一代人？使用我们的ALS-PDC模型，我们将解决(1)神经退行性变的关键问题 时间线和(2)神经毒素作为年龄函数的影响。为了探究这些问题，成年男性CD-1 小鼠将喂食洗净的苏铁或分离出的假定苏铁毒素、变种甾基糖苷。一个详细的 行为、形态和生化事件的时间线将从最初的暴露到 这两个组都处于结束状态。为了进一步研究神经退行性变级联中的关键事件， 神经细胞将在暴露于类固醇期间和之后的组织培养准备中进行检查。 糖苷。拟议的年龄效应研究将检查两个方面：苏铁神经毒素诱导的行为 以及在1至18个月的时间内作为年龄函数的病理效应。在第二个系列中 通过实验，我们将确定早期接触苏铁毒素是否会加剧晚期成人的暴露症。 这些数据将为预防或阻止神经变性的进展提供治疗靶点。

ALS parkinsonism-dementia complex (ALS-PDC) is a neurological disease that can present as classical ALS, an Alzeheimer's-like disorder with associated parkinsonism features, or a combination. It is a cluster of age-dependent neurodegenerative disorders, representing the only widely acknowledged such cluster and may offer vital clues to the etiology of related disorders. We have successfully modeled the disease by feeding washed cycad flour to adult mice, which develop behavioral and histopathological deficits resembling ALS-PDC. The ability to model the disease allows us to ask fundamental questions of great potential impact for related disorders: Which environmental toxins and genetic susceptibilities contribute to neurodegeneration? What is the time course of the behavioral and pathological deficits from initial expo- sure until behavioral end state? How does age affect disease development and progression? Finally, based on the above, can we design prophylactic and early treatment strategies to prevent further neurode- generation? Using our model of ALS-PDC, we will address the crucial questions of (1) neurodegeneration time-line and (2) the impact of neurotoxins as a function of age. To probe these questions, adult male CD-1 mice will be fed washed cycad or the isolated putative cycad toxins, variant steryl glucosides. A detailed time-line of behavioral, morphological, and biochemical events will be studied from initial exposure through to an end state for both groups. To further examine crucial events in the neurodegeneration cascade, neural cells will be examined in a tissue culture preparation during and following exposure to steryl glucosides. The proposed age effects study will examine two aspects: cycad neurotoxin-induced behavioral and pathological effects as a function of age over a span of 1 to 18 months. In a second series of experiments, we will determine if an early exposure to cycad toxins can exacerbate a late adult expo- sure. These data will provide therapeutic targets to prevent or halt the progression of neurodegeneration.