Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive loss of multiple cognitive functions. Accumulation of amyloid beta oligomers (oAβ) play a major role in the neurotoxicity associated with the disease process. One of the early affected brain regions is the hippocampus, wherein a reduction of the vacuolar protein sorting-associated protein 35 (VPS35), the core protein comprising the retromer complex involved in cellular cargo sorting, has been identified. To investigate the role of the retromer function on the accumulation and clearance of oAβ, we reduced retromer function by selectively inhibiting VPS35 gene expression using siRNA in differentiated neuronal SH-SY5Y cells. As cell-to-cell transfer of oAβ to new brain regions is believed to be important for disease progression we investigated the effect of VPS35 reduction both in cells with direct uptake of oAβ and in cells receiving oAβ from donor cells. We demonstrate that reduced retromer function increases oAβ accumulation in both cell systems, both the number of cells containing intracellular oAβ and the amount within them. This effect was shown at different time points and regardless if the oAβ originated from the extracellular milieu or via a direct neuronal cell-to-cell transfer. Interestingly, not only did reduced VPS35 cause oAβ accumulation, but oAβ treatment alone also lead to a reduction of VPS35 protein content. The accumulated oAβ seems to co-localize with VPS35 and early endosome markers. Together, these findings provide evidence that reduced retromer function decreases the ability for neurons to transport and clear neurotoxic oAβ received through different routes resulting in the accumulation of oAβ. Thus, enhancing retromer function may be a potential therapeutic strategy to slow down the pathophysiology associated with the progression of AD.

阿尔茨海默氏病（AD）是一种神经退行性疾病，其特征在于多种认知功能的逐步丧失。淀粉样β寡聚体（oAβ）的积累在与疾病过程相关的神经毒性中起主要作用。早期受影响的大脑区域之一是海马体，其中已鉴定出空泡蛋白分选相关蛋白35（VPS35）的减少，该蛋白是包含参与细胞货物分选的逆转录复合物的核心蛋白。为了研究逆转录功能对oAβ积累和清除的作用，我们通过在分化的神经元SH-SY5Y细胞中使用siRNA选择性抑制VPS35基因表达来减少逆转录功能。由于人们认为oAβ到新大脑区域的细胞间转移对疾病进展很重要，因此我们研究了直接摄取oAβ的细胞和从供体细胞接受oAβ的细胞中VPS35降低的影响。我们证明减少的retromer功能增加了两个细胞系统中oAβ的积累，既包含细胞内oAβ的细胞数量也包含其中的数量。在不同的时间点都显示出这种效果，而无论oAβ是源自细胞外环境还是通过直接的神经元细胞间转移而产生。有趣的是，降低的VPS35不仅会导致oAβ积累，而且单独进行oAβ处理也会导致VPS35蛋白质含量降低。累积的oAβ似乎与VPS35和早期内体标记共定位。一起，这些发现提供了证据，即降低的逆转录酶功能降低了神经元转运和清除通过不同途径接收的神经毒性oAβ的能力，从而导致oAβ的积累。因此，增强逆转录酶功能可能是减缓与AD进展相关的病理生理的潜在治疗策略。