Beclin1 and autophagie in Alzheimers disease

Beclin1 和阿尔茨海默病中的自噬

• 批准号: 363200821
• 负责人: Professor Dr. Frank Heppner
• 金额: --
• 依托单位: Institut für Neuropathologie (CCM)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/363200821?language=en
• 关键词: Beclin1; autophagie; Alzheimers; disease

Alzheimers disease (AD) is the most common neurodegenerative disorder, hallmarked by extracellular amyloid plaques (composed of amyloid-beta (Abeta) peptide), neurofibrillary tangles, neuroinflammation and neurodegeneration. The amyloid cascade hypothesis states that deposition of Abeta in the brain parenchyma is one of the crucial steps in the development of AD. Microglia, the resident immune cells of the central nervous system are involved in two aspects of AD: the removal respectively the failure of removal of extracellular Abeta by phagocytosis and the production and release of cytokines. Next to the well-established enhanced neuroinflammation in the late stages of AD, recent data suggests a role for inflammation in the development of AD as well. A candidate process involved in both neuroinflammation and removal of Abeta is autophagy. The efficiency of autophagy seems to decline during aging. In addition, autophagy is a regulatory mechanism for the inflammatory response in macrophages. Beclin1, a crucial protein for autophagy, was also shown to be involved in receptor recycling and retromer recruitment for phagocytosis in vitro. Based on these data we postulate that Beclin1 is a key molecule in microglia, influencing neuroinflammation and Abeta deposition via autophagy and phagocytosis. This hypothesis will be tested by analyzing the impact of microglial Beclin1 loss in vivo employing two different approaches: inducible and constitutive loss of Beclin1.For the inducible model Beclin1 will be depleted at different time points with an inducible flox system targeting myeloid cells crossed to the established AD mouse model APPPS1+/- to determine the microglia-specific impact on autophagy and phagocytosis (aim 1), inflammation (aim 2) and Abeta deposition (aim 3) after complete loss of microglial Beclin1 in vivo. As additional system to pinpoint myeloid-driven effects an inducible flox system will be used to achieve a general loss of Beclin1.Next to that we will employ mice with a general constitutive heterozygous deletion of Beclin1 that will be crossed to APPPS1 mice, to mimic the situation in microglia from human AD patients. Again the effect of diminished Beclin1 levels in vivo on autophagy and phagocytosis (aim 1), inflammation (aim 2) and onset or progression of Abeta plaque deposition (aim 3) will be investigated.By using these two mouse systems this project will not only clarify the role of Beclin1 in microglial autophagy and phagocytosis in vivo but it is also very well suited to elucidate the causal and temporal relationship of microglial inflammation in AD and Abeta deposition.

阿尔茨海默病（Alzheimers disease，AD）是最常见的神经退行性疾病，以细胞外淀粉样蛋白斑（由淀粉样蛋白β（A β）肽组成）、神经纤维缠结、神经炎症和神经退行性病变为特征。淀粉样蛋白级联假说指出，A β在脑实质中的沉积是AD发展的关键步骤之一。小胶质细胞是中枢神经系统的常驻免疫细胞，参与AD的两个方面：通过吞噬作用去除细胞外A β和产生和释放细胞因子，分别去除细胞外A β和细胞外A β的失败。除了在AD的晚期阶段中公认的增强的神经炎症之外，最近的数据表明炎症在AD的发展中也起作用。参与神经炎症和Abeta去除的候选过程是自噬。自噬的效率似乎在衰老过程中下降。此外，自噬是巨噬细胞中炎症反应的调节机制。Beclin 1是自噬的关键蛋白，也被证明参与受体回收和体外吞噬作用的逆转录聚合物募集。基于这些数据，我们假设Beclin 1是小胶质细胞中的关键分子，通过自噬和吞噬作用影响神经炎症和Abeta沉积。将采用两种不同的方法，通过分析体内小胶质细胞Beclin 1损失的影响来检验这一假设：Beclin 1的诱导型和组成型损失对于诱导型模型，Beclin 1将在不同时间点用靶向骨髓细胞的诱导型flox系统与建立的AD小鼠模型APPPS 1 +/-杂交而耗尽，以确定小胶质细胞对自噬和吞噬作用的特异性影响（目的1），炎症（目标2）和Abeta沉积（目标3）后，小胶质细胞Beclin 1在体内完全丧失。作为确定骨髓驱动效应的额外系统，将使用诱导型flox系统来实现Beclin 1的普遍缺失。接下来，我们将使用Beclin 1的一般组成性杂合缺失的小鼠与APPPS 1小鼠杂交，以模拟人类AD患者的小胶质细胞中的情况。同样，体内Beclin 1水平降低对自噬和吞噬作用的影响（目的1），炎症（目的2）和Abeta斑块沉积的发生或进展（目的3）通过使用这两个小鼠系统，该项目不仅将阐明Beclin 1在体内小胶质细胞自噬和吞噬作用中的作用，而且它也非常适合于阐明小胶质细胞自噬和吞噬作用之间的因果关系和时间关系。AD炎症和Abeta沉积。