Saman Sudad, Lee Norman C Y, Inoyo Itoro, Jin Jun, Li Zhihan, Doyle Thomas, McKee Ann C, Hall Garth F
Department of Biological Sciences, University of Massachusetts Lowell, Lowell, MA, USA Mass Bay Community College, Science Department, STEM Division, MA, USA.
Boston University Chemical Instrumentation Center, Department of Chemistry, Boston, MA, USA.
J Alzheimers Dis. 2014;40 Suppl 1(Suppl 1):S47-70. doi: 10.3233/JAD-132135.
Tau misprocessing to form aggregates and other toxic species has emerged as a major feature in our developing understanding of the etiology and pathogenesis of Alzheimer's disease (AD). The significance of tau misprocessing in AD has been further emphasized by recent studies showing that tau can be secreted from neurons via exosomes and may itself be an important agent in the spreading of neurofibrillary lesions within the brain. Tau secretion occurs most readily under disease-associated conditions in cellular models, suggesting that cellular changes responsible for secretion, possibly including tau oligomerization, could play a key role in the propagation of neurofibrillary lesions in neurodegenerative disease. Here we show that overexpression of 4R0N human tau in neuroblastoma cells recruits mitochondrial and axonogenesis-associated proteins relevant to neurodegeneration into the exosomal secretion pathway via distinct mechanisms. The recruitment of mitochondrial proteins appears to be linked to autophagy disruption (exophagy) in multiple neurodegenerative conditions but has few known direct links to AD and tau. By contrast, the involvement of synaptic plasticity and axonogenesis markers is highly specific to both tau and AD and may be relevant to the reactivation of developmental programs involving tau in AD and the recently demonstrated ability of secreted tau to establish tissue distribution gradients in CNS neuropil. We also found a highly significant correlation between genes that are significantly downregulated in multiple forms of AD and proteins that have been recruited to exosomes by tau, which we interpret as strong evidence for the central involvement of tau secretion in AD cytopathogenesis. Our results suggest that multiple cellular mechanisms may link tau secretion to both toxicity and neurofibrillary lesion spreading in AD and other tauopathies.
在我们对阿尔茨海默病（AD）病因和发病机制的逐步认识中，tau蛋白错误加工形成聚集体和其他有毒物质已成为一个主要特征。最近的研究进一步强调了tau蛋白错误加工在AD中的重要性，这些研究表明tau蛋白可通过外泌体从神经元中分泌出来，并且其本身可能是神经原纤维病变在脑内扩散的重要介质。在细胞模型中，tau蛋白分泌在疾病相关条件下最容易发生，这表明负责分泌的细胞变化，可能包括tau蛋白寡聚化，可能在神经退行性疾病的神经原纤维病变传播中起关键作用。在这里，我们表明在神经母细胞瘤细胞中过表达4R0N人tau蛋白会通过不同机制将与神经退行性变相关的线粒体和轴突发生相关蛋白募集到外泌体分泌途径中。线粒体蛋白的募集似乎与多种神经退行性疾病中的自噬破坏（外自噬）有关，但与AD和tau蛋白的已知直接联系较少。相比之下，突触可塑性和轴突发生标志物的参与对tau蛋白和AD都具有高度特异性，并且可能与AD中涉及tau蛋白的发育程序重新激活以及最近证明的分泌型tau蛋白在中枢神经系统神经纤维网中建立组织分布梯度的能力有关。我们还发现，在多种形式的AD中显著下调的基因与被tau蛋白募集到外泌体中的蛋白质之间存在高度显著的相关性，我们将此解释为tau蛋白分泌在AD细胞发病机制中起核心作用的有力证据。我们的结果表明，多种细胞机制可能将tau蛋白分泌与AD和其他tau蛋白病中的毒性和神经原纤维病变扩散联系起来。
