Abstract：
Alzheimer\'s disease (AD) is the most prevalent age-associated neurodegenerative disease. A decrease in autophagy during aging contributes to brain disorders by accumulating potentially toxic substrates in neurons. Rubicon is a well-established inhibitor of autophagy in all cells. However, Rubicon participates in different pathways depending on cell type, and little information is currently available on neuronal Rubicon\'s role in the AD context. Here, we investigated the cell-specific expression of Rubicon in postmortem brain samples from AD patients and 5xFAD mice and its impact on amyloid β burden in vivo and neuroblastoma cells. Further, we assessed Rubicon levels in human-induced pluripotent stem cells (hiPSCs), derived from early-to-moderate AD and in postmortem samples from severe AD patients. We found increased Rubicon levels in AD-hiPSCs and postmortem samples and a notable Rubicon localization in neurons. In AD transgenic mice lacking Rubicon, we observed intensified amyloid β burden in the hippocampus and decreased Pacer and p62 levels. In APP-expressing neuroblastoma cells, increased APP/amyloid β secretion in the medium was found when Rubicon was absent, which was not observed in cells depleted of Atg5, essential for autophagy, or Rab27a, required for exosome secretion. Our results propose an uncharacterized role of Rubicon on APP/amyloid β homeostasis, in which neuronal Rubicon is a repressor of APP/amyloid β secretion, defining a new way to target AD and other similar diseases therapeutically.
摘要：
阿尔茨海默病(AD)是最常见的年龄相关性神经退行性疾病。衰老过程中自噬的减少通过在神经元中积累潜在的毒性底物而导致脑部疾病。Rubicon是所有细胞中自噬的公认抑制剂。然而,Rubicon根据细胞类型参与不同的途径，目前关于神经元Rubicon在AD上下文中的作用的信息很少。这里,我们研究了来自AD患者和5xFAD小鼠的死后脑样本中Rubicon的细胞特异性表达及其对体内淀粉样β负荷和神经母细胞瘤细胞的影响。Further,我们评估了人诱导多能干细胞（hiPSCs）中的Rubicon水平，源自早期至中度AD和重度AD患者的死后样本。我们发现AD-hiPSC和死后样本中Rubicon水平增加，神经元中Rubicon定位显着。在缺乏Rubicon的AD转基因小鼠中，我们观察到海马中β淀粉样蛋白负荷增强，Pacer和p62水平降低。在表达APP的神经母细胞瘤细胞中，当Rubicon不存在时，发现培养基中APP/淀粉样β分泌增加，这在缺乏自噬必需的Atg5的细胞中没有观察到，或者Rab27a,需要外泌体分泌。我们的结果提出Rubicon对APP/淀粉样蛋白β稳态的未表征作用，其中神经元Rubicon是APP/淀粉样β分泌的阻遏物，为AD和其他类似疾病的治疗提供新的靶点。
