Acta Neuropathologica综述 ︱前沿！阿尔茨海默症新基因图谱：从淀粉样蛋白级联到基因驱动的突触功能衰竭假说

Authorship (Chinese)︱LTNeurosci

Responding Editor︱LTNeurosci

阿尔茨海默症（AD）是最常见的神经退行性疾病，且有很强的遗传易感性（约占可归因风险的60-80%）。记忆丧失和认知障碍是AD必然的早期临床症状；同时，神经元死亡所引起的海马萎缩是AD最早的病理特征之一。此外，在死后AD大脑中也已观察到了前神经元死亡、突触功能障碍以及突触丢失，而且，这些特征与认知能力下降关联密切【1】。

神经细胞内异常Tau蛋白所形成的神经原纤维缠结，以及β-淀粉样蛋白（Aβ）所组成的淀粉样斑块是AD最经典的两个病理病变。

Fig.1 Circular diagram of AD genetic risk factors. The diagram shows (from outside to inside): (1) genomic loci in alphabetical order; (2) genes therein; (3) expression profiles of these genes in different cell types of the brain (grayscale); and (4) the pathways/processes/proteins to which these genes have been functionally linked (colour). Details of the functional studies supporting these linkages are available in Suppl. Table. Expression profiles were extracted from【6】(FPKM fragments per kilobase of transcript sequence per million mapped fragments). The circlize package of the R software (http://www.r-proje ct.org/) was used to generate the diagram【7】.

基因APP、PSEN1和PSEN2的罕见突变会引发常染色体显性疾病；随后，在此基础上，学者们建立了淀粉样蛋白级联假说（the amyloid cascade hypothesis），进而从根本上改变了我们对AD的理解【2】。淀粉样前体蛋白（APP）的异常代谢，特别是长Aβ肽的过量产生会引发相应的病理突变，这表明这些多肽在AD进展中的起着核心作用；而且，这些神经毒性肽的过量产生可能会导致（或加重）Tau病理在神经元间的传播。然而，其详细机制仍不清楚【3】。

但是，由于单基因形式（突变）在所有AD病例中所占比例不到1%，所以，仍存在关键问题：淀粉样蛋白级联假说是否是所有AD形式的核心？晚期非孟德尔型AD是否还涉及其他病理生理过程？

Fig. 2 Amyloid cascade hypothesis and genetic risk factors of AD. Autosomal dominant mutations that cause early onset familial AD (in APP, PSEN1 and PSEN2) gave rise to the amyloid cascade hypothesis, which aims to link amyloid plaques and neurofibrillary tangles, the two classical AD hallmarks. Involvement of the genetic risk factors of late-onset AD in APP metabolism and in Aβ clearance through the blood brain barrier or microglia supports this hypothesis. Soluble forms of Aβ may be inducing neurotoxicity through modifying Tau metabolism, leading to neurofibrillary tangle formation and neuronal death. Recent GWAS-defined genes that modulate Tau toxicity may be involved in Aβ-induced neurotoxicity through mechanisms that are yet to be identified.

因此，在此背景下，研究AD最常见形式的遗传学将会加深我们对AD潜在病理生理过程的理解。在AD常见形式中，遗传风险占可归因风险的80%【4】。由此，可以认为绝大多数AD病理生理通路是由（或包括）遗传决定因素所导致的。因此，揭示这些遗传决定因素会促进我们对AD基本疾病过程的认知。

在由（德国）里尔大学里尔巴斯德研究所的学者Pierre Dourlen，Devrim Kilinc等人撰写的最新一篇综述中，作者们详细介绍了有关AD遗传学和全基因组关联研究（the post-genome wide association studies，GWASs）的最新进展，并进一步探讨了这些研究成果如何帮助我们充分理解AD的病理生理过程【5】。该篇前沿性综述于2019年4月13日以The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? 为题在线发表在Acta Neuropathologica（IF=15.872）上【5】。

首先，Pierre Dourlen等人分析了遗传风险因子是如何参与到APP的新陈代谢，Aβ肽的产生、降解、聚合和神经毒性,以及先天免疫和Tau毒性。

在最近高通量基因组研究方法和新兴神经生物信息学的帮助下，科学家们获得了最新的AD基因图谱（genetic landscape），由此，文章作者提出了一个重要模型：局灶性粘附/黏附（focal adhesion）通路和相关细胞信号通路是AD发病机制过程中的关键因素。局灶性粘附/黏附通路的核心是APP和Tau的生理功能及其参与的病理生理过程。

Fig. 3 Interactions between integrin, APP and receptor tyrosine kinases (RTKs) at the cell surface modulate cell adhesion. The GWAS-defined genes FERMT2, Cass4, PTK2B and CD2AP, recently identified for their roles in APP metabolism (in green) and/or Tau pathology (in red), are involved in the focal adhesion complex, which regulates several downstream cell signalling pathways as well as the actin cytoskeleton. This observation supports the concept that the focal adhesion core, together with its related downstream pathways, may be an important actor in the AD process.

Fig. 4 Genetic risk factors and synapse dysfunction in AD pathogenesis. Regulation of the focal adhesion pathway plays central roles in synaptic plasticity (synaptic maintenance, actin cytoskeleton remodelling, vesicle, and receptor cycling). Dysfunction of downstream cellular signalling pathways involving APP and/or Tau may thus participate in synapse loss. Additionally, dysregulation of the core FA pathway could modulate APP and Tau metabolisms, leading to an exacerbation of synaptotoxicity through Aβ overproduction and Tau-modulated excitotoxicity. Finally, Aβ availability at the synapses is dependent on its clearance through the blood brain barrier and/or by microglial cells.

该模型包括多个侵入点（entry points），并且，这些侵入点与疾病的不同起源相吻合；同时，此模型表明突触可塑性失调是AD的中心节点。

其次，文章作者通过对GWASs最新数据的分析，进而对AD研究领域已出现多个假设（包括淀粉样蛋白的级联、细胞相位（cellular phase）、传播等）进行了有效补充和完善。文章最后，Pierre Dourlen等人认为基因驱动的突触功能衰竭假说需要在一般性AD框架下进行进一步的实验验证。

Fig. 5 Reappraisal of the amyloid cascade hypothesis into a circular model. In this new model, dysfunction of the FA pathway at synapses could be the basis of a vicious cycle with multiple entry points linking AD hallmarks to synapse dysregulation, synapse loss, and subsequent cognitive decline.

补充阅读

参考文献

【1】Forner S, et al. (2017) Synaptic impairment in Alzheimer’s disease: a dysregulated symphony. Trends Neurosci 40:347–357.

【2】Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356.

【3】Clavaguera F, et al (2009) Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 11:909–913.

【4】Gatz M, et al (2006) Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry 63:168–174.

【5】Pierre Dourlen, et al (2019) The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? Acta Neuropathologica  https://doi.org/10.1007/s00401-019-02004-0

【6】Zhang Y, et al (2016) Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron 89:37–53.

【7】Gu Z, et al (2014) circlize implements and enhances circular visualization in R. Bioin- formatics 30:2811–2812.

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