TGFbeta signaling in neurodegeneration and Alzhimer's

神经退行性变和阿尔茨默病中的 TGFbeta 信号传导

• 批准号: 7147180
• 负责人: TONY WYSS-CORAY
• 金额: $ 25.78万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7147180
• 关键词: Alzheimer' s disease; aging; amyloid proteins; cell growth regulation; cell population study; cytokine receptors; developmental neurobiology; gene deletion mutation; gene induction /repression; genetically modified animals; laboratory mouse; neural degeneration; neuronal transport; neuroprotectants; neurotoxicology; phosphorylation; protein biosynthesis; tau proteins; tissue /cell culture; transcription factor; transforming growth factors

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a neurodegenerative disease that leads to progressive cognitive dysfunction. Current knowledge of the processes leading to Alzheimer's disease is still limited, and no effective treatments are available. Alzheimer's disease is characterized by loss of neurons and the abnormal accumulation of amyloid beta into amyloid plaques and hyperphosphorylated tau into neurofibrillary tangles. However, in the vast majority of AD cases there are no obvious alterations in the molecular pathways causing amyloid beta production or tau hyperphosphorylation and it has been difficult to assign them a causal role in sporadic Alzheimer's disease. It is perhaps more likely that other factors trigger these toxic pathways which subsequently lead to neurodegeneration. Age is the major known risk factor for Alzheimer's disease. It is associated with an increase in cellular injury and inflammation and it has been postulated that an age-related reduction in trophic support makes neurons vulnerable to injury and degeneration. TGF-beta1 is an injury response factor and has been implicated in AD pathogenesis. TGF-beta1 levels in AD brains are increased and correlate inversely with the amount of parenchymal amyloid beta deposition but positively with the amount of cerebrovascular amyloid betadeposition. This is consistent with findings in transgenic mice where TGF-beta1 produced by astrocytes reduces the accumulation of parenchymal amyloid beta while the remaining amyloid beta is found in blood vessels. TGF-beta1 has also potent neurotrophic/neuroprotective effects in numerous cell culture and in vivo models of brain injury and mice lacking TGF-beta1 show spontaneous neuronal cell death and neurodegeneration. Our most recent preliminary studies demonstrate that reduced TGF-beta signaling in neurons promotes AD-like disease in mice suggesting that neuronal TGF-beta signaling may be beneficial. Based on these findings we propose the hypothesis that aging and reduced trophic support to neurons promotes neurodegeneration and sporadic Alzheimer's disease and that neuronal TGF-beta signaling is a critical trophic signal for neurons to age successfully. To test our hypothesis we will determine how lack of neuronal TGF-beta signaling affects survival, APR processing, and tau phosphorylation in cell culture studies and we will use unbiased screens to identify the transcription factors and TGF-beta responsive genes mediating neuroprotection in neurons. We will block neuronal TGF-beta signaling in AD mouse models in vivo before or during active disease to accelerate disease, and we will specifically increase neuronal TGF-beta signaling before or during active disease to ameliorate disease. These in vivo studies will help us to assess the relevance and potential therapeutic implications of our hypothesis and will evaluate the TGF-bet1 signaling pathway as a potential target for the treatment of Alzheimer's disease.

描述（由申请人提供）：阿尔茨海默氏病（AD）是一种神经退行性疾病，导致逐步认知功能障碍。当前对导致阿尔茨海默氏病的过程的了解仍然有限，并且没有有效的治疗方法。阿尔茨海默氏病的特征是神经元的丧失以及淀粉样蛋白β异常积累到淀粉样蛋白斑中，而高磷酸化的tau进入神经纤维纤维缠结中。但是，在绝大多数AD病例中，分子途径没有明显改变，导致淀粉样蛋白β产生或Tau高磷酸化，并且很难在零星阿尔茨海默氏病中分配因果作用。其他因素可能触发这些有毒途径的可能性更大，这随后导致神经退行性。年龄是阿尔茨海默氏病的主要危险因素。它与细胞损伤和炎症的增加有关，并假定与年龄相关的营养支持减少使神经元容易受到损伤和变性。 TGF-BETA1是损伤反应因子，并且与AD发病机理有关。 AD大脑中的TGF-BETA1水平增加并与实质淀粉样蛋白β沉积量相反，但与脑血管淀粉样蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白淀粉样蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白酶的数量呈肯定相关。这与转基因小鼠中的发现一致，其中由星形胶质细胞产生的TGF-BETA1降低了实质淀粉样蛋白β的积累，而其余的淀粉样蛋白β则在血管中发现。 TGF-BETA1在众多细胞培养和脑损伤的体内模型中还具有有效的神经营养/神经保护作用，缺乏TGF-BETA1的小鼠显示自发的神经元细胞死亡和神经变性。我们最近的初步研究表明，神经元中TGF-β信号的降低会促进小鼠的AD样疾病，这表明神经元TGF-β信号传导可能是有益的。 基于这些发现，我们提出了以下假设：衰老和减少对神经元的营养支持会促进神经退行性和零星的阿尔茨海默氏病，而神经元TGF-beta信号传导是神经元成功的营养信号。为了检验我们的假设，我们将确定缺乏神经元TGF-β信号传导如何影响细胞培养研究中的生存，APR加工和TAU磷酸化，我们将使用无偏的筛选来识别转录因子和TGF-β响应基因介导神经元中神经元的介导的基因。我们将在活动性疾病之前或加速疾病期间的AD小鼠模型中阻止AD小鼠模型中的神经元TGF-β信号传导，并且在活动性疾病之前或期间，我们将特别增加神经元TGF-β信号传导以改善疾病。这些体内研究将有助于我们评估假设的相关性和潜在治疗意义，并将评估TGF-BET1信号传导途径，以此作为治疗阿尔茨海默氏病的潜在靶标。