Instituto de Tecnologías Biomédicas (ITB), Universidad de La Laguna (ULL), 38200 Tenerife, Spain.
Centro de Biología Molecular Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Científicas (CSIC) y la Universidad Autónoma de Madrid (UAM), 28049 Madrid, Spain.
Cells. 2021 Mar 24;10(4):721. doi: 10.3390/cells10040721.
Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed serine/threonine kinase with a plethora of substrates. As a modulator of several cellular processes, GSK-3 has a central position in cell metabolism and signaling, with important roles both in physiological and pathological conditions. GSK-3 has been associated with a number of human disorders, such as neurodegenerative diseases including Alzheimer's disease (AD). GSK-3 contributes to the hyperphosphorylation of tau protein, the main component of neurofibrillary tangles (NFTs), one of the hallmarks of AD. GSK-3 is further involved in the regulation of different neuronal processes that are dysregulated during AD pathogenesis, such as the generation of amyloid-β (Aβ) peptide or Aβ-induced cell death, axonal transport, cholinergic function, and adult neurogenesis or synaptic function. In this review, we will summarize recent data about GSK-3 involvement in these processes contributing to AD pathology, mostly focusing on the crucial interplay between GSK-3 and tau protein. We further discuss the current development of potential AD therapies targeting GSK-3 or GSK-3-phosphorylated tau.
糖原合酶激酶-3（GSK-3）是一种广泛表达的丝氨酸/苏氨酸激酶，其底物众多。作为多种细胞过程的调节剂，GSK-3 在细胞代谢和信号转导中处于中心地位，在生理和病理条件下都具有重要作用。GSK-3 与许多人类疾病有关，如包括阿尔茨海默病（AD）在内的神经退行性疾病。GSK-3 参与了 tau 蛋白的过度磷酸化，tau 蛋白是神经原纤维缠结（NFTs）的主要成分之一，也是 AD 的标志之一。GSK-3 还参与了 AD 发病过程中失调的不同神经元过程的调节，如淀粉样β（Aβ）肽的产生或 Aβ 诱导的细胞死亡、轴突运输、胆碱能功能、成年神经发生或突触功能。在这篇综述中，我们将总结最近关于 GSK-3 参与这些导致 AD 病理的过程的数据，主要集中在 GSK-3 和 tau 蛋白之间的关键相互作用上。我们还讨论了针对 GSK-3 或 GSK-3 磷酸化 tau 的潜在 AD 治疗方法的最新进展。
