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

描述（由申请人提供）：ALS帕金森氏症-痴呆复合体（ALS- pdc）是一种神经系统疾病，可以表现为典型的ALS，一种阿尔茨海默病样疾病，伴有相关的帕金森氏症特征，或两者兼有。这是一组年龄依赖性神经退行性疾病，代表了唯一被广泛承认的这类疾病，并可能为相关疾病的病因提供重要线索。我们通过给成年小鼠喂食洗过的苏铁粉，成功地建立了这种疾病的模型，成年小鼠出现了类似ALS-PDC的行为和组织病理学缺陷。这种疾病的建模能力使我们能够提出对相关疾病具有巨大潜在影响的基本问题：哪些环境毒素和遗传易感性会导致神经变性？行为和病理缺陷从最初接触到行为结束状态的时间过程是怎样的？年龄如何影响疾病的发展和进展？最后，基于上述，我们能否设计预防和早期治疗策略来防止进一步的神经变性发生？使用我们的ALS-PDC模型，我们将解决(1)神经退行性变时间线和(2)神经毒素作为年龄函数的影响的关键问题。为了探讨这些问题，我们给成年雄性CD-1小鼠喂食洗净的苏铁或分离的苏铁毒素，变异的steryl glucosides。详细的时间线的行为，形态和生化事件将研究从最初接触到结束状态的两组。为了进一步研究神经退行性级联中的关键事件，神经细胞将在暴露于steryl葡糖苷期间和之后的组织培养准备中进行检查。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和病理效应作为年龄的函数，跨度为1至18个月。在第二个系列的实验中，我们将确定早期接触苏铁毒素是否会加剧成年后期的接触。这些数据将为预防或阻止神经退行性疾病的进展提供治疗靶点。

DESCRIPTION (provided by applicant): ALS parkinsonism-dementia complex (ALS-PDC) is a neurological disease that can present as classical ALS, an Alzheimer'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 exposure 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 exposure. These data will provide therapeutic targets to prevent or halt the progression of neurodegeneration.