Blurton-Jones Mathew, Laferla Frank M
Department of Neurobiology and Behavior, University of California, Irvine, CA 92697-4545, USA.
Curr Alzheimer Res. 2006 Dec;3(5):437-48. doi: 10.2174/156720506779025242.
Since the initial description one hundred years ago by Dr. Alois Alzheimer, the disorder that bears his name has been characterized by the occurrence of two brain lesions: amyloid plaques and neurofibrillary tangles (NFTs). Yet the precise relationship between beta-amyloid (Abeta) and tau, the two proteins that accumulate within these lesions, has proven elusive. Today, a growing body of work supports the notion that Abeta may directly or indirectly interact with tau to accelerate NFT formation. Here we review recent evidence that Abeta can adversely affect distinct molecular and cellular pathways, thereby facilitating tau phosphorylation, aggregation, mis-localization, and accumulation. Studies are presented that support four putative mechanisms by which Abeta may facilitate the development of tau pathology. A great deal of work suggests that Abeta may drive tau pathology by activating specific kinases, providing a straightforward mechanism by which Abeta may enhance tau hyperphosphorylation and NFT formation. In the AD brain, Abeta also triggers a massive inflammatory response and pro-inflammatory cytokines can in turn indirectly modulate tau phosphorylation. Mounting evidence also suggests that Abeta may inhibit tau degradation via the proteasome. Lastly, Abeta and tau may indirectly interact at the level of axonal transport and evidence is presented for two possible scenarios by which axonal transport deficits may play a role. We propose that the four putative mechanisms described in this review likely mediate the interactions between Abeta and tau, thereby leading to the development of AD neurodegeneration.
自100年前阿洛伊斯·阿尔茨海默博士首次描述以来，以他的名字命名的这种疾病的特征是出现两种脑损伤：淀粉样斑块和神经原纤维缠结（NFTs）。然而，在这些损伤中积累的两种蛋白质——β-淀粉样蛋白（Aβ）和tau蛋白之间的确切关系一直难以捉摸。如今，越来越多的研究支持这样一种观点，即Aβ可能直接或间接与tau蛋白相互作用，加速NFTs的形成。在这里，我们回顾了最近的证据，即Aβ会对不同的分子和细胞途径产生不利影响，从而促进tau蛋白的磷酸化、聚集、错误定位和积累。文中介绍的研究支持了Aβ促进tau蛋白病变发展的四种假定机制。大量研究表明，Aβ可能通过激活特定激酶来驱动tau蛋白病变，这为Aβ增强tau蛋白过度磷酸化和NFTs形成提供了一种直接机制。在阿尔茨海默病大脑中，Aβ还会引发大规模炎症反应，促炎细胞因子进而可间接调节tau蛋白的磷酸化。越来越多的证据还表明，Aβ可能通过蛋白酶体抑制tau蛋白的降解。最后，Aβ和tau蛋白可能在轴突运输水平上间接相互作用，文中展示了轴突运输缺陷可能发挥作用的两种可能情况的证据。我们认为，本综述中描述的四种假定机制可能介导了Aβ与tau蛋白之间的相互作用，从而导致阿尔茨海默病神经退行性变的发展。
