Laboratorio di Biologia BIO@SNS, Scuola Normale Superiore, Pisa, Italy.
Istituto di Neuroscienze, CNR, Pisa, Italy.
J Mol Biol. 2020 Dec 4;432(24):166675. doi: 10.1016/j.jmb.2020.10.009. Epub 2020 Oct 13.
Neuronal hyperexcitability linked to an increase in glutamate signalling is a peculiar trait of the early stages of Alzheimer's disease (AD) and tauopathies, however, a progressive reduction in glutamate release follows in advanced stages. We recently reported that in the early phases of the neurodegenerative process, soluble, non-aggregated Tau accumulates in the nucleus and modulates the expression of disease-relevant genes directly involved in glutamatergic transmission, thus establishing a link between Tau instability and altered neurotransmission. Here we report that while the nuclear translocation of Tau in cultured cells is not impaired by its own aggregation, the nuclear amyloid inclusions of aggregated Tau abolish Tau-dependent increased expression of the glutamate transporter. Remarkably, we observed that in the prefrontal cortex (PFC) of AD patient brain, the glutamate transporter is upregulated at early stages and is downregulated at late stages. The Gene Set Enrichment Analysis indicates that the modulation of Tau-dependent gene expression along the disease progression can be extended to all protein pathways of the glutamatergic synapse. Together, this evidence links the altered glutamatergic function in the PFC during AD progression to the newly discovered function of nuclear Tau.
神经元过度兴奋与谷氨酸信号的增加有关，这是阿尔茨海默病（AD）和tau 病早期的一个特殊特征，然而，在晚期，谷氨酸释放会逐渐减少。我们最近报道称，在神经退行性过程的早期阶段，可溶性、非聚集的 Tau 积累在细胞核中，并直接调节与谷氨酸能传递直接相关的疾病相关基因的表达，从而在 Tau 不稳定性和改变的神经递质传递之间建立了联系。在这里，我们报告说，虽然 Tau 在培养细胞中的核转位不受其自身聚集的影响，但聚集的 Tau 的核淀粉样蛋白包含物会消除 Tau 依赖性增加的谷氨酸转运体的表达。值得注意的是，我们观察到在 AD 患者大脑的前额叶皮层（PFC）中，谷氨酸转运体在早期阶段上调，在晚期阶段下调。基因集富集分析表明，随着疾病的进展，Tau 依赖性基因表达的调节可以扩展到谷氨酸能突触的所有蛋白质途径。总之，这些证据将 AD 进展过程中 PFC 中谷氨酸能功能的改变与新发现的核 Tau 功能联系起来。
