Beclin 1 Neurodegeneration and Alzheimer's Disease

描述（由申请人提供）：阿尔茨海默病（AD）是一种与年龄相关的疾病，导致认知功能的急剧丧失，影响全球数百万老年人。其病理特征在于存在β淀粉样蛋白（AB）和tau蛋白聚集体以及进行性神经变性。有非常强有力的证据表明，AB的异常组装是神经毒性的，并在AD中起关键作用。为什么AB积累或诱导神经变性尚不清楚。在一份将Beclin 1（一种参与自噬早期步骤的必需蛋白质）与lurcher小鼠的神经变性和细胞死亡联系起来的报告之后，我们决定探索Beclin 1和自噬在AD中发挥作用的可能性。自噬是参与长寿命蛋白质和细胞器的降解、细胞重塑和营养饥饿期间的存活的主要途径。目前尚不清楚自噬是否在神经变性和阿尔茨海默病中发挥病理或保护作用。我们发现，与年龄匹配的路易体变异型AD、亨廷顿病、帕金森病或非痴呆对照组相比，AD病例死后大脑额叶皮质灰质中Beclin 1的表达减少了50%以上。这种减少不仅仅是由于神经元的损失，因为神经元蛋白神经元特异性烯醇化酶的水平没有改变。我们发现，在Beclin 1-/+单倍不足小鼠中Beclin 1表达的遗传减少导致原代神经元中的自噬减少，并且与9个月大小鼠的神经变性相关。在APP转基因小鼠中Beclin 1缺乏，AD模型，导致APP和AB片段在细胞和细胞外间隙中的积累增加，并与炎症增加相关。此外，培养的神经母细胞瘤细胞中增加的自噬减少APP片段，而siRNA介导的Beclin 1表达减少增加APP片段和AB。总之，这些研究为Beclin 1和自噬在AD发病机制中的作用提供了强有力的证据，并为潜在靶向这种疾病开辟了新的途径。本申请的目的是确定Beclin 1在神经元和小鼠大脑中如何调节，它如何影响AB及其前体的产生和周转，以及Beclin 1的产生增加是否可以保护和改善小鼠的神经变性和AD样疾病。我们还期望确定Beclin 1是AD发病机制的主要调节剂，并且增加Beclin 1水平可以减少疾病。如果成功，我们的发现可能为治疗AD和神经退行性疾病提供新的靶点。

DESCRIPTION (provided by applicant): Alzheimer's Disease (AD) is an age-related disorder that causes a dramatic loss of cognitive function and affects millions of elderly individuals worldwide. It is characterized pathologically by the presence of protein aggregates of beta amyloid (AB) and tau and a progressive neurodegeneration. There is exceedingly strong evidence that abnormal assemblies of AB are neurotoxic and have a key role in AD. Why AB accumulates or induces neurodegeneration is unclear. Following up on a report that linked Beclin 1, an essential protein involved in the early steps of autophagy, to neurodegeneration and cell death in the lurcher mouse we decided to explore the possibility that Beclin 1 and autophagy may have a role in AD. Autophagy is the major pathway involved in the degradation of long-lived proteins and organelles, cellular remodeling, and survival during nutrient starvation. It is unclear whether autophagy exerts a pathological or protective role in neurodegeneration and Alzheimer's Disease. We discovered that expression of Beclin 1 is reduced more than 50% in gray matter of the frontal cortex in postmortem brains from AD cases compared with age-matched cases of Lewy body variant of AD, Huntington's disease, Parkinson's disease, or nondemented controls. This decrease was not simply due to a loss of neurons since levels of the neuronal protein neuron specific enolase were not altered. We found that genetic reduction of Beclin 1 expression in beclin 1-/+ haploinsufficient mice results in less autophagy in primary neurons and is associated with neurodegeneration in 9-month-old mice. Beclin 1 deficiency in APP transgenic mice, a model for AD, results in increased accumulation of fragments of APP and AB in cells and in the extracellular space and was associated with increased inflammation. In addition, increased autophagy in cultured neuroblastoma cells reduces APP fragments while siRNA mediated reduction in Beclin 1 expression increases APP fragments and AB. Together, these studies provide strong evidence for a role of Beclin 1 and autophagy in AD pathogenesis and they open a new pathway to potentially target this disease. The goal of this application is to determine how Beclin 1 is regulated in neurons and in mouse brains, how it affects the production and turnover of AB and its precursors, and whether increased production of Beclin 1 may be protective and ameliorate neurodegeneration and AD-like disease in mice. We also expect to establish that Beclin 1 is a major modifier of AD pathogenesis and that increasing Beclin 1 levels reduces disease. If successful, our findings may provide new targets for the treatment of AD and neurodegeneration.