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

ALS-PDC 小鼠模型神经退行性变的时间线

• 批准号: 7139507
• 负责人: CHRISTOPHER Ariel SHAW
• 金额: $ 9.78万
• 依托单位: UNIVERSITY OF BRITISH COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7139507
• 关键词: aging; model; neural degeneration; toxin

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.

描述（由申请人提供）：ALS帕金森病-痴呆综合征（ALS-PDC）是一种神经系统疾病，可表现为经典ALS、具有相关帕金森病特征的阿尔茨海默病样障碍或其组合。它是一组年龄依赖性神经退行性疾病，代表了唯一被广泛认可的此类疾病，并可能为相关疾病的病因学提供重要线索。我们已经成功地模拟了这种疾病的饲料洗涤苏铁粉成年小鼠，发展类似ALS-PDC的行为和组织病理学缺陷。对这种疾病进行建模的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导致了神经退行性变？从最初暴露到行为结束状态的行为和病理缺陷的时间过程是什么？年龄如何影响疾病的发展和进展？最后，基于以上所述，我们是否可以设计预防和早期治疗策略来防止进一步的神经退行性变？使用我们的ALS-PDC模型，我们将解决以下关键问题：（1）神经变性时间线和（2）神经毒素作为年龄函数的影响。为了探索这些问题，成年雄性CD-1小鼠将喂食洗涤的苏铁或分离的推定苏铁毒素，变体甾醇葡糖苷。将研究两组从初始暴露到结束状态的行为、形态和生化事件的详细时间线。为了进一步检查神经变性级联中的关键事件，将在暴露于甾醇葡糖苷期间和之后在组织培养制备物中检查神经细胞。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学影响作为年龄的函数超过1至18个月。在第二个系列的实验中，我们将确定早期暴露于苏铁毒素是否会加剧晚期成人暴露。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。