论文题目：Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease

scholar 引用：102

页数：18

发表时间：2019

发表刊物：nature neuroscience

作者：EvandroF.Fang etc.

摘要：

Accumulation of damaged mitochondria(线粒体) is a hallmark of aging and age-related neurodegeneration(衰老), including Alzheimer’s disease (AD). The molecular mechanisms of impaired mitochondrial homeostasis in AD are being investigated. Here we provide evidence that mitophagy(线粒体自噬) is impaired in the hippocampus(海马体) of AD patients, in induced pluripotent(多能性) stem cell-derived human AD neurons, and in animal AD models. In both amyloid-β (Aβ) and tau Caenorhabditis elegans(秀丽隐杆线虫) models of AD, mitophagy stimulation (through NAD+ supplementation, urolithin A, and actinon in) reverses memory impairment through PINK-1 (PTEN-induced kinase-1)-, PDR-1 (Parkinson’s disease-related-1; parkin)-, or DCT-1 (DAF-16/FOXO-controlled germline-tumor affecting-1)- dependent pathways. Mitophagy diminishes insoluble Aβ1–42 and Aβ1–40 and prevents cognitive impairment in an APP/PS1 mouse model through microglial phagocytosis of extracellular Aβ plaques and suppression of neuroinflammation. Mitophagy enhancement abolishes AD-related tau hyperphosphorylation in human neuronal cells and reverses memory impairment in transgenic tau nematodes and mice. Our findings suggest that impaired removal of defective mitochondria is a pivotal event in AD pathogenesis and that mitophagy represents a potential therapeutic intervention.

Nat Neuro: 阿尔兹海默症重大突破！提高脑细胞线粒体自噬消除阿尔兹海默症症状

Nature 重大发现：大脑细胞缺乏细胞自噬清洁是导致阿兹海默症发生的关键，老年痴呆有救啦！

摘要：受损线粒体的累积是衰老和与年龄相关的神经变性（包括阿尔茨海默病（AD））的标志。正在研究AD中线粒体稳态受损的分子机制。在这里，我们提供了AD患者海马，诱导多能干细胞衍生的人AD神经元和动物AD模型中线粒体自噬受损的证据。在AD的淀粉样蛋白-β（Aβ）和tau Caenorhabditis elegans模型中，线粒体自噬刺激（通过NAD +补充，尿石素A和放线菌素）通过PINK-1（PTEN诱导的激酶-1）- ，PDR-1逆转记忆障碍。（帕金森氏病相关-1; parkin）- 或DCT-1（DAF-16 / FOXO控制的种系- 肿瘤影响-1）依赖性途径。线粒体自噬减少不溶性Aβ1-42和Aβ1-40通过细胞外Aβ斑块的小胶质细胞吞噬作用和神经炎症的抑制来预防APP / PS1小鼠模型中的认知障碍。线粒体增强消除了人类神经元细胞中与AD相关的tau蛋白过度磷酸化，并逆转了转基因tau线虫和小鼠的记忆障碍。我们的研究结果表明，有缺陷的线粒体去除受损是AD发病机制中的关键事件，并且线粒体自噬代表了潜在的治疗干预。

结论：

• impaired removal of defective mitochondria is a pivotal event in AD pathogenesis and that mitophagy represents a potential therapeutic intervention.缺陷线粒体的清除受损是AD发病机制中的关键事件，线粒体代表了潜在的治疗干预措施。
• We demonstrate that defective mitophagy, which can be caused by both Aβ1–42 and p-tau, is a major element of AD progression and memory loss in a manner that is conserved from C. elegans and mice to humans. 引起AD progression and memory loss 的主要原因
• Further studies to uncouple the interconnected sophisticated roles between defective mitophagy, AMPK, p-tau, and Aβ in AD etiology and progression are necessary. 在补充材料中有一个model
• Our findings extend the ‘AD mitochondrial cascade hypothesis’2,41 through the linkage of defective mitophagy to damaged mitochondria.
• However, they also raise many important questions, such as: (1) the chronological sequence of defective mitophagy, Aβ, and tau tangles; (2) whether defective mitophagy and AD pathologies exacerbate one another; and (3) whether any sex differences in mitophagy exist in AD patients since the prevalence of AD and other dementias is higher in women than in men. 1.时间顺序？2.线粒体缺陷和AD病理相互加剧？是否涉及到因果关系？3.性别差异？
• While it is difficult to address these questions with the current transgenic AD animal models, other animal models more similar to human AD, as well as human longitudinal studies, may provide an insight. 
• We found that three distinct pharmacological approaches were effective in counteracting the pathogenic processes of AD and ameliorating cognitive impairment, suggesting a potential for clinical interventions that enhance mitophagy via different mechanisms. 有三种药理方法可以达到这个目的
• 问题1：缺陷线粒体清除机制跟阿尔兹海默症之间有关联，在人体中，会不会有其他的因素影响了缺陷线粒体清除，从而加重了阿尔兹海默症？临床上可以组织什么样的实验来确定这种因果关系？
• there is a sophisticated set of connections between mitochondrial impairment and these two AD pathological factors, suggesting that targeting defective mitochondria may be an important approach for AD therapy. 复杂的联系，如何确定因果？

正文组织架构：

1. Introduction

2. Results

2.1 Defective mitophagy in the hippocampal samples of AD patients and in AD iPSC-derived neurons.

2.2 Restoration of neuronal mitophagy ameliorates(改善) cognitive decline in C. elegans models of AD.

2.3 Restoration of neuronal mitophagy ameliorates cognitive decline and Aβ pathology in the APP/PS1 mouse model.

2.4 Restoration of neuronal mitophagy enhances the phagocytic(吞噬) efficiency of microglia and mitigates neuroinflammation.

2.5 Restoration of neuronal mitophagy ameliorates p-tau pathology and cognitive deficits in AD across species.

3. Discussion

4. Methods

4.1 C. elegans strains and genetics

4.2 Molecular cloning.

4.3 Screening of neuronal mitophagy inducers.

4.4 C. elegans memory assays.

4.5 Mitophagy/autophagy detection.

4.6 iPSC-derived neurons.

4.7 Evaluation of p-tau in cell lines.

4.8 Mice.

4.9 MWM and Y maze.

4.10 Object recognition and fear conditioning tests.

4.11 Electron microscopy.

4.12 Microarray.

4.13 Immunohistochemistry (IHC) and immunofluorescence.

4.14 Western blots.

4.15 Enzyme-linked immunosorbent assay (ELISA) for Aβ and proinflammatory/ anti-inflammatory cytokines.

4.16 OCR.

4.17 Mitochondrial parameters.

4.18 Randomization and blinding.

4.19 Statistical analysis.

4.20 Reporting Summary.

正文部分内容摘录：
Questions:

1.How does this study try to determine the causality or directionality between mitochondrial deficiency and Alzheimer’s disease (AD) pathology?

2.If the amyloid-β hypothesis does not hold, what effect will it have on the conclusions of this paper?

3. How do you view the importance of the results of this gene expression analysis to the conclusion?