BACKGROUND Dysfunctional autophagy is implicated in Alzheimer's Disease (AD) pathogenesis. The alterations in the expression of many autophagy related genes (ATGs) have been reported in AD brains; however, the disparity of the changes confounds the role of autophagy in AD. METHODS To further understand the autophagy alteration in AD brains, we analyzed transcriptomic (RNAseq) datasets of several brain regions (BA10, BA22, BA36 and BA44 in 223 patients compared to 59 healthy controls) and measured the expression of 130 ATGs. We used autophagy-deficient mouse models to assess the impact of the identified ATGs depletion on memory, autophagic activity and amyloid-β (Aβ) production. RESULTS We observed significant downregulation of multiple components of two autophagy kinase complexes BECN1-PIK3C3 and ULK1/2-FIP200 specifically in the parahippocampal gyrus (BA36). Most importantly, we demonstrated that deletion of NRBF2, a component of the BECN1-PIK3C3 complex, which also associates with ULK1/2-FIP200 complex, impairs memory in mice, alters long-term potentiation (LTP), reduces autophagy in mouse hippocampus, and promotes Aβ accumulation. Furthermore, AAV-mediated NRBF2 overexpression in the hippocampus not only rescues the impaired autophagy and memory deficits in NRBF2-depleted mice, but also reduces β-amyloid levels and improves memory in an AD mouse model. CONCLUSIONS Our data not only implicates NRBF2 deficiency as a risk factor for cognitive impairment associated with AD, but also support the idea of NRBF2 as a potential therapeutic target for AD.

中文翻译：

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自噬蛋白NRBF2在阿尔茨海默氏症的大脑中表达减少，并调节小鼠的记忆力和淀粉样β稳态。

背景功能失调的自噬与阿尔茨海默氏病（AD）的发病机制有关。据报道，AD大脑中许多自噬相关基因（ATG）的表达发生了改变。然而，变化的差异混淆了自噬在AD中的作用。方法为了进一步了解AD大脑的自噬改变，我们分析了223个患者的多个大脑区域（BA10，BA22，BA36和BA44，与59个健康对照相比）的转录组（RNAseq）数据集，并测量了130个ATG的表达。我们使用自噬缺陷小鼠模型来评估已确定的ATG耗竭对记忆力，自噬活性和淀粉样β（Aβ）产生的影响。结果我们观察到两种自噬激酶复合物BECN1-PIK3C3和ULK1 / 2-FIP200的多个成分的明显下调，特别是在海马旁回（BA36）中。最重要的是，我们证明了NRBF2（BECN1-PIK3C3复合体的组成部分）的缺失，它也与ULK1 / 2-FIP200复合体相关联，损害了小鼠的记忆力，改变了长期增强（LTP），降低了小鼠海马体的自噬，并促进Aβ积累。此外，在海马中，AAV介导的NRBF2过表达不仅可以挽救NRBF2耗竭小鼠的自噬和记忆障碍，而且还可以降低AD小鼠模型的β-淀粉样蛋白水平并改善记忆。结论我们的数据不仅暗示NRBF2缺乏是与AD相关的认知障碍的危险因素，