Studies of Hirano Bodies in Living Cells

描述(申请人提供)：阿尔茨海默病的特点是严重的进行性神经变性，不仅对患者，而且对家庭和照顾者都有毁灭性的影响。目前，阿尔茨海默病还没有治愈方法，目前的治疗方法在所有患者中都能适度延缓病情进展。为了开发新的治疗方法，必须确定能够调节毒性发展的途径。对遗传性神经退行性疾病家族、阿尔茨海默病小鼠模型和细胞培养模型的研究表明，淀粉样β蛋白和微管结合蛋白tau参与了导致认知功能丧失的途径。平野小体是一种富含肌动蛋白的结构，在大脑中出现的数量越来越多，与包括阿尔茨海默病在内的许多疾病有关。平野小体的生理功能尚不清楚。然而，众所周知，平野小体积累了淀粉样前体蛋白的COOH末端区域，也积累了tau。因此，平野小体可能会影响阿尔茨海默病的进展。我们最近建立了细胞培养模型和转基因小鼠模型来研究平野小体。该项目的长期目标是了解平野小体对疾病进展的影响。这项提议的目的是验证这样一种假设，即平野小体要么促进阿尔茨海默病的病理发展，要么保护阿尔茨海默病的病理发展。为了实现这一目标，平野小体的小鼠模型将与转基因阿尔茨海默病模型小鼠杂交，后者具有由淀粉样前体蛋白或tau诱导的神经退化症状。结果将通过免疫组织化学、电生理学和行为研究进行评估，以评估平野小体对体内神经病理发展和认知能力下降的影响。这些研究将对平野小体可以调节阿尔茨海默病的神经毒性这一假设进行批判性检验。此外，这些研究还将揭示平野小体是否可以影响由淀粉样前体蛋白和/或tau途径启动的毒性。如果结果表明平野小体可以调节这种疾病的发展，那么参与平野小体形成或退化的途径将被确定为治疗阿尔茨海默病的药物开发的新靶点。 公共卫生相关性：阿尔茨海默病的治疗迫切需要新的药物治疗，因为阿尔茨海默病对数百万疾病受害者和家庭成员的健康有重大影响，而且目前的治疗方法只有轻微的效果。为了确定药物开发的新靶点，确定阿尔茨海默病中损害脑细胞的事件以及调节这一过程的途径是至关重要的。该项目旨在确定阿尔茨海默病患者大脑中越来越多的被称为平野小体的结构是否会影响阿尔茨海默病的进展，以及导致平野小体形成或退化的途径是否是治疗阿尔茨海默病的药物开发的新候选者。

DESCRIPTION (provided by applicant): Alzheimer's disease is characterized by profound progressive neurodegeneration that has devastating effects not only on patients but also on families and caregivers. At present, there is no cure for Alzheimer's disease, and current treatments provide modest delay in progression in a subset of all patients. It is essential to identify pathways that can modulate the development of toxicity in order to develop new treatments. Studies of families with genetically inherited neurodegenerative disease, mouse models of Alzheimer's disease, and cell culture models implicate the amyloid beta peptide, the amyloid precursor protein from which amyloid beta is derived, and the microtubule binding protein tau in pathways that lead to loss of cognitive function. Hirano bodies are actin-rich structures that appear in the brain in increased numbers in association with many conditions including Alzheimer's disease. The physiological function of Hirano bodies is not known. However, it is known that Hirano bodies accumulate COOH terminal regions of the amyloid precursor protein and also tau. Therefore, Hirano bodies could influence the progression of Alzheimer's disease. We have recently developed cell culture models and a transgenic mouse model for studies of Hirano bodies. The long term goal of this project is to understand the impact of Hirano bodies on the progression of disease. The goal of this proposal is to test the hypothesis that Hirano bodies either promote or protect from development of pathology in Alzheimer's disease. To achieve this objective, a mouse model of Hirano bodies will be crossed with transgenic Alzheimer's model mice that have symptoms of neurodegeneration induced either by amyloid precursor protein or tau. The outcomes will be assessed using immunohistochemistry, electrophysiology, and behavioral studies to assess the effect of Hirano bodies on development of neuropathology and cognitive decline in vivo. These studies will critically test the hypothesis that Hirano bodies can modulate neurotoxicity in Alzheimer's disease. In addition, the studies will reveal whether Hirano bodies can affect toxicity initiated by pathways involving amyloid precursor protein and/or tau. If the results show that Hirano bodies can modulate the progression of this disease, then pathways involved in formation or degradation of Hirano bodies would be identified as novel targets for drug development to treat Alzheimer's disease. PUBLIC HEALTH RELEVANCE: New drug treatments are urgently needed for treatment of Alzheimer's disease, since Alzheimer's disease has a major impact on the health of millions of disease victims and family members, and because current therapies are only marginally effective. To identify novel targets for drug development, it is essential to determine the events that damage brain cells in Alzheimer's disease, as well as pathways that can regulate this process. This project seeks to determine whether structures called Hirano bodies that are present in increased numbers in the brain of Alzheimer's patients can affect the progression of Alzheimer's disease, and whether pathways leading to formation or degradation of Hirano bodies are novel candidates for drug development to treat Alzheimer's disease.