这么多人热捧LED治疗阿兹海默病,但它真的会有效么?

上传 / 管理员 ·2016-12-18 医学,阿兹海默,LED

论文标题 / Gamma frequency entrainment attenuates amyloid load and modifies microglia

作者 / Hannah F. Iaccarino,Annabelle C. Singer,et al

期刊 / Nature

发表时间 / 2016-12-08

数字识别码 / doi:10.1038/nature20587

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来源 MIT News
翻译 闫亢

今年12月7日,蔡立慧(Li-Huei Tsai)教授在在线版《自然》杂志(Nature)上作为第一作者发表了一篇论文。他们观察到,使用特定频率的LED闪光灯可以大幅度降低阿尔茨海默症小鼠视觉皮层中的β淀粉样蛋白斑块。

这种治疗方法是通过诱导大脑内产生一种被称为 γ 振荡的脑电波作用的,研究人员们发现,γ 振荡不仅可以帮助大脑抑制 β 淀粉样蛋白的产生,还可以激活负责摧毁这些蛋白斑块的细胞。

麻省理工学院科学学院院长 Michael Sipser 说:“这项研究可能预示着在理解与治疗阿尔茨海默症上将取得了突破性进展。这种可怕的疾病正在全球折磨着几百万人与他们的家庭。我们麻省理工学院的科学家们为这项大脑疾病的研究开辟了全新的方向,为其中致病与预防的机制研究打开了新的大门。我认为这非常令人振奋。”

Ed Boyden 是麻省理工学院媒体实验室(MIT Media Lab)与麦戈文脑研究所(the McGovernInstitute for Brain Research)生物工程及脑与认知副教授,也是这篇论文的作者之一。他与蔡立慧教授成立了一家叫做 Cognito Therapeutics 的公司将在人类患者中对该试验方法进行测试。

脑电波刺激

在美国,超过五百万的人患有阿尔茨海默症。这种疾病的特点是,患者脑部会产生β淀粉样蛋白斑块,从而可能导致脑细胞损伤,扰乱正常大脑功能。之前的研究显示,阿尔茨海默症患者往往会伴随γ振荡受损的症状。γ振荡是频率范围在25 Hz到80 Hz范围内的脑波,它被认为有助于维持如注意力、认知和记忆功能等正常的大脑功能。

在蔡立慧教授与她的同事的研究中,使用了基因修饰后的阿尔茨海默症模型小鼠,它们没有表现出任何蛋白斑块的聚集与行为学症状。研究发现对这些小鼠进行迷宫实验时,当出现需要记忆与学习的活动模式的时候,γ振荡出现了损伤。

接着,研究人员用40 Hz 的 γ 振荡频率刺激海马区,这是大脑中对记忆形成与恢复至关重要的部位。在初步研究中,他们使用了由 Boyden 等人首创的一种叫做光遗传学(optogenetics)的技术,科学家们可以利用这种技术通过用光照射基因修饰后的神经元来控制他们的活动。研究人员使用这一方法刺激了大脑中的中间神经元,它会将γ振荡的活动同步给兴奋性神经元。

经过一小时的40 Hz 刺激后,研究人员发现海马体上的β淀粉样蛋白水平下降了40%到50%。但是使用20 Hz到80 Hz中的其它频率刺激时,并没有产生这样的效果。

蔡立慧教授与她的同事开始思考是否可以使用更少介入的技术达到同一效果。她与 Emery Brown,这位 Edward Hood Taplin 医学工程和计算神经科学教授,是 Picower 研究所的成员之一,也是这篇论文的作者一起想到可以使用外界刺激——光,来驱动脑部的 γ 振荡。他们用一系列以不同频率闪烁的 LED 灯搭建了一个简易的设备。

利用该设备,研究人员们发现,在阿尔茨海默症发病极早期的小鼠接受了一小时40 Hz 强度的 LED 光照射后,它们脑部的 γ 振荡增强,β淀粉样蛋白的水平也降低了一半。但是,在照射结束后的24小时内,β淀粉样蛋白又回到了原来的水平。

研究人员们接着又探究了是否可以通过更长时间的光照射减少小鼠体内更高水平的β淀粉样蛋白聚集。在对小鼠进行了连续七天,每天一小时的LED光照射后,淀粉斑块与自由浮动的淀粉样蛋白都显著性减少。目前他们正在试着确定这一现象究竟可以持续多长时间。

此外,研究人员们还发现 γ 节律的脑电波同时降低了阿尔茨海默症的另一项重要生物学指标的水平:异常修饰的 Tau 蛋白,这是一种会在脑内形成缠结的蛋白。

哈佛大学医学院的神经学教授 Alvaro Pascual-Leone 没有参与这项研究,他说:“这项研究是在精心设计和用心执行下完成的,它表明我们长久以来知道与认知功能相关的γ振荡,在大脑中消除 β 淀粉样蛋白沉积中起到了重要的作用。这非常的引人瞩目与令人震惊,它使将这一方法应用在人类身上变得有希望了起来。”

蔡立慧教授的实验室正在研究光照是否可以越过视觉皮层到达大脑并驱动其的γ振荡,初步研究数据显示这是可能的。同时,研究人员们还在研究β淀粉样蛋白斑块的减少是否会影响阿尔茨海默症小鼠的行为学症状,以及这项技术是否对其它与γ振荡受损相关的神经系统疾病有作用。

两种作用方式

研究人员们还试着通过实验探究 γ 振荡是如何发挥其作用的。他们发现,在被 γ 振荡刺激后,β 淀粉样蛋白的形成过程变慢。γ 振荡还会增强大脑清除 β 淀粉样蛋白的能力,这种能力通常是一种叫做小神经胶质细胞的免疫细胞所具有的。

蔡立慧教授解释说:“小神经胶质细胞可以清除有毒物质和细胞碎片,保证细胞内环境整洁并保持神经元的健康。”

在阿尔茨海默症患者体内,小神经胶质细胞会非常容易发炎并且会分泌有毒的化学物质使更多的脑细胞损伤。但是,当小鼠的 γ 振荡增强后,它们的小神经胶质细胞会发生形态学改变并且会更加积极清除 β 淀粉样蛋白。

蔡立慧教授说:“本质上来说,增强大脑中的 γ 振荡至少可以通过两种方式减少淀粉样蛋白。一种是减少神经元产生 β 淀粉样蛋白,另一种是增强小神经胶质细胞清除淀粉样蛋白的能力。”

研究人员们还检测了光照实验小鼠大脑中信使 RNA 的序列,他们发现,其中数百种基因都存在过表达或者低表达的现象,研究人员正在分析这些变异对阿尔茨海默症可能产生的影响。

不过,蔡立慧教授在接受采访时也说:“这是一个很大的“如果”,因为太多已经证明在小鼠身上起作用的实验都在人类身上失败了。”对于这项让人觉得有些惊讶的研究来说,未来还需要更多的试验才能证实是否有效。

如果未来通过临床试验,这项研究将改写的,可能是一项数以十亿美元计算的医学产业。

原文链接 http://news.mit.edu/2016/visual-stimulation-treatment-alzheimer-1207


摘要 Changes in gamma oscillations (20–50 Hz) have been observed in several neurological disorders. However, the relationship between gamma oscillations and cellular pathologies is unclear. Here we show reduced, behaviourally driven gamma oscillations before the onset of plaque formation or cognitive decline in a mouse model of Alzheimer’s disease. Optogenetically driving fast-spiking parvalbumin-positive (FS-PV)-interneurons at gamma (40 Hz), but not other frequencies, reduces levels of amyloid-β (Aβ)1–40 and Aβ 1–42 isoforms. Gene expression profiling revealed induction of genes associated with morphological transformation of microglia, and histological analysis confirmed increased microglia co-localization with Aβ. Subsequently, we designed a non-invasive 40 Hz light-flickering regime that reduced Aβ1–40 and Aβ1–42 levels in the visual cortex of pre-depositing mice and mitigated plaque load in aged, depositing mice. Our findings uncover a previously unappreciated function of gamma rhythms in recruiting both neuronal and glial responses to attenuate Alzheimer’s-disease-associated pathology.

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谭坤 回复 匿名
This study makes a major claim by suggesting that “tuning up” the endogenous gamma frequency (40 Hz) activity in neural circuits using optogenetics or external light sources in an Alzheimer mouse model can greatly reduce Amyloid β levels by stimulating microglial phagocytosis.

We reviewed this paper in journal club and have major concerns about the validity of the data:

1) The main result rests on data showing that microglia have internalized Aβ in the specific regions where 40 Hz-entrainment occurred, but not with other oscillation frequencies or in regions outside the trained circuit. Key measurements such as in situ Abeta levels and microglia morphology and phagocytosis relied solely on optical imaging. Unfortunately, the quality of the imaging data is very poor. The images purporting the appearance of immuno-labeled Aβ and its pattern within microglial cells are highly questionable and inconsistent between different parts of the paper. See images from the paper below and our reinterpretation of their data.

http://i.imgur.com/wE9ToV3.jpg

2)Potentially problematic labeling of Aβ in Figure 2e, 3d and 4d. The Aβ-labeling looks suspicious, compared to all literature reports showing Aβ/APP immunohistochemistry in AD mouse models. The appearance of Aβ looks very much like cellular processes, instead of the expected spherical, lysosomal look of phagocytosed Aβ aggregates inside microglia. This apparent “cellular-shaped” Aβ labeling is likely to be artifactual, possibly due to a.) they use YPF expressing mice and do not explain well how they excluded the signal coming from YFP; b.) bleed through from the microglia channel; and/or c.) more likely poor primary Aβ antibody labeling leading to unspecific cross-labeling of microglia by the secondary antibody (through FC receptors). In addition, in some images the Aβ labeling appeared to be elongated, with intensely-labeled structures which were likely to be blood vessels but no parenchymal plaques were seen in the images. Strikingly, in Figure 4k, the membrane looking cellular-shaped appearance of Aβ labeling is abolished when the microglial Iba1-colabeling is not done. This is further evidence that in the younger mice the Aβ labeling was artifactual, therefore quantifications based on these images are likely not reliable .

3) Potentially biased microglia imaging in Figure 3d. Aside from the problems with Aβ imaging, the microglia images also raise concerns. In the examples shown in Figure 3d, the background (area not filled by microglia processes) was significantly different between groups. Perhaps coincidental, but the 40 Hz-treatment group has the highest background and the random treatment control group has the lowest, which matches the quantification of microglia processes. This suggests to us that these images can be projections from stacks of different thickness, or different imaging planes.

4) One possible explanation for some of their results that was not fully controlled for was the optogenetic stimulation. This paradigm may lead to calcium overload and excitotoxic injury which would cause microglia activation and not-surprisingly would induce cell loss and enhanced tissue phagocytosis potentially explaining their increased microglia and reduced amyloid labeling. Such hypertrophic microglia morphology is reminiscent of activated microglia in epilepsy models. The authors should provide raw Z-stack images (instead of the processed 3D renderings) in each treatment group to clarify this point.

5) Questionable experimental design and statistical power: For many of the experiments in this study, only 3-4 mice were used for each treatment group. Gender of mice used in each arm was not reported. It is well known that gender influences the pace of plaque accumulation in the 5xFAD line. Females have a more aggressive deposition phenotype. Unequal distribution of male and female in any group could skew the results. In later experiments using 6-month old mice larger Ns are reported, but still not gender. For example, in Figure 4i-m its possible the alleged 50% reduction in plaque load could be explained by assigning a higher number of female mice in the control groups and more male mice in the 40 Hz-flicker group. Knowing the gender distribution for each experiment will be important to confirm the validity of these results.

In summary, the claims of this paper should be taken with caution given that they are largely based on potentially flawed imaging data, lack of proper controls and inadequate methodological details about their staining and quantification protocols.

这个?

2016-12-19 20:07:24

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PubPeer 上说这个图不大对。。。大家看看呢?
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2016-12-19 20:05:00

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不晓得能不能有相似的方法治疗其他精神疾病?

2016-12-19 18:56:57

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还没在人身上试过吧?

2016-12-19 18:56:07

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在看又不有效之前,治疗方案是第一位吧,有可能在人类身上使用方法不对?

2016-12-18 12:29:43

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