新证据!阿尔兹海默症致病蛋白会传播
2018/01/09
阿尔兹海默症的致病蛋白——Tau蛋白会在患者大脑中扩散,从一个神经元传播到另一个神经元,从而引发痴呆症状的加重。科学家们希望,这一最新研究找到的“新证据”有望为通过阻断蛋白传染而减缓疾病发展提供支撑。


这一突破成果得益于脑成像技术的发展——正电子发射计算机断层扫描(PET)技术的发展让科学家们能够观察患者的大脑(不再依赖于解剖已去世患者的大脑)。

剑桥大学的科学家们借助于PET技术分析了17名阿尔兹海默症患者的大脑,找到了Tau蛋白在大脑不同区域内传染的证据。相关研究成果发表在最新一期的《Brain》杂志。

关于Tau蛋白的假设

已有研究表明,这一神经退行性疾病与两种在大脑中异常累积的蛋白有关:Tau蛋白和β-淀粉样蛋白(Aβ)。最主流的推断是:β-淀粉样蛋白最先累积,引发神经元突触功能障碍、Tau蛋白过度磷酸化和继发炎性反应,导致神经元变性死亡,从而吞噬记忆、认知等功能。

科学家们一直在猜测Tau蛋白在大脑中出现的细节,有3个假设:

1)“跨神经元传播”(transneuronal spread)假说:Tau蛋白在一个位置累积,随后扩散到其他脑区域,引发连锁反应。这一推测最有利的说明是一项以小鼠为模型的研究——当小鼠被注入异常的人Tau蛋白,该蛋白会在其大脑内迅速传播。

2)“代谢脆弱”(metabolic vulnerability)假说:Tau蛋白在神经细胞内产生(并不传播),但是不同细胞对该蛋白的敏感度不同(新陈代谢需求不同),从而造成不同的影响。

3)“营养支持”(trophic support)假说:Tau蛋白不传播,但是一些大脑区域比其他区域更容易受其伤害,这主要与营养缺乏或者基因表达模式有关。

有科学家对第一个推测提出质疑,因为小鼠研究中注射的Tau蛋白量远远超出正常痴呆患者大脑内的致病蛋白量。而且,科学家们认为,蛋白质在小鼠大脑中会快速传播,但是在人类大脑中传播较慢。但是,一直未有定论。

新发现作证假设

来自剑桥大学临床神经科学专家James Rowe教授和团队找到了答案——在研究了阿尔兹海默症患者大脑内部的功能联系,并将其与Tau蛋白水平相比较后,佐证了“跨神经元传播”假设,即Tau蛋白会在神经元之间传播。

文章第一作者Thomas Cope认为,这一发现意味着,Tau蛋白会伴随着功能相连的神经元而扩散开,并逐层累积到外围。这一传播方式类似于流感病毒,病毒最先传染的是病人身边的人,随后再传递给其他有过接触的人。

Tau蛋白最初出现于AD患者大脑的内嗅皮质区,位于海马区(主管记忆功能)旁边。这或许是痴呆患者最先出现记忆衰退的原因。而且,Tau蛋白会在大脑中传播,感染和破坏神经细胞,导致患者的症状越来越严重。

在阿尔兹海默症患者大脑中, Tau蛋白的传播比较随机,这或许可以解释患者为什么会出现记忆、认知混乱的症状。这一研究提醒大家,或可通过阻断Tau蛋白的传播而减缓痴呆症的恶化。

参考资料:

Advances in brain imaging settle debate over spread of key protein in Alzheimer's

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  • Tau burden and the functional connectome in Alzheimer’s disease and progressive supranuclear palsy

    Alzheimer’s disease and progressive supranuclear palsy (PSP) represent neurodegenerative tauopathies with predominantly cortical versus subcortical disease burden. In Alzheimer’s disease, neuropathology and atrophy preferentially affect ‘hub’ brain regions that are densely connected. It was unclear whether hubs are differentially affected by neurodegeneration because they are more likely to receive pathological proteins that propagate trans-neuronally, in a prion-like manner, or whether they are selectively vulnerable due to a lack of local trophic factors, higher metabolic demands, or differential gene expression. We assessed the relationship between tau burden and brain functional connectivity, by combining in vivo PET imaging using the ligand AV-1451, and graph theoretic measures of resting state functional MRI in 17 patients with Alzheimer’s disease, 17 patients with PSP, and 12 controls. Strongly connected nodes displayed more tau pathology in Alzheimer’s disease, independently of intrinsic connectivity network, validating the predictions of theories of trans-neuronal spread but not supporting a role for metabolic demands or deficient trophic support in tau accumulation. This was not a compensatory phenomenon, as the functional consequence of increasing tau burden in Alzheimer’s disease was a progressive weakening of the connectivity of these same nodes, reducing weighted degree and local efficiency and resulting in weaker ‘small-world’ properties. Conversely, in PSP, unlike in Alzheimer’s disease, those nodes that accrued pathological tau were those that displayed graph metric properties associated with increased metabolic demand and a lack of trophic support rather than strong functional connectivity. Together, these findings go some way towards explaining why Alzheimer’s disease affects large scale connectivity networks throughout cortex while neuropathology in PSP is concentrated in a small number of subcortical structures. Further, we demonstrate that in PSP increasing tau burden in midbrain and deep nuclei was associated with strengthened cortico-cortical functional connectivity. Disrupted cortico-subcortical and cortico-brainstem interactions meant that information transfer took less direct paths, passing through a larger number of cortical nodes, reducing closeness centrality and eigenvector centrality in PSP, while increasing weighted degree, clustering, betweenness centrality and local efficiency. Our results have wide-ranging implications, from the validation of models of tau trafficking in humans to understanding the relationship between regional tau burden and brain functional reorganization.

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