Toledo Enrique M, Colombres Marcela, Inestrosa Nibaldo C
Centro de Envejecimiento y Regeneración (CARE), Instituto Milenio MIFAB, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Chile.
Prog Neurobiol. 2008 Nov;86(3):281-96. doi: 10.1016/j.pneurobio.2008.08.001. Epub 2008 Aug 19.
In the past several years, we postulated that the loss of Wnt signaling was implicated in the pathology of Alzheimer's disease (AD). Since then, our lab and other groups have confirmed the involvement of the Wnt signaling in some aspects of AD. So far, we have demonstrated that activation of Wnt signaling protects neurons against neurotoxic injuries, including both amyloid-beta (Abeta) fibrils and Abeta oligomers by using either lithium, an inhibitor of the glycogen-synthase-kinase-3beta (GSK-3beta), or different Wnt ligands. Also, we have found that several molecules which activate well known neurotransmitter systems and other signaling system, are able by crosstalk to activate Wnt/beta-catenin signaling in order to protect neurons against both Abeta fibrils or Abeta oligomers. In particular, the activation of non-canonical Wnt signaling was able to protect postsynaptic regions and dendritic spines against Abeta oligomers. Furthermore Wnt signaling ligands also affect stem cells, and they are also involved in cell fate decision during neurogenesis and embryonic development as well as in adult stem cells differentiation in the nervous system. The Wnt signaling plays a key role modulating their cell differentiation or proliferation states. Altogether, these findings in both stem cell biology and neuroprotection, may introduce new approaches in the treatment of neurodegenerative diseases, including drug screening and therapies against neurodegenerative diseases which activates the Wnt signaling pathway.
在过去几年中，我们推测Wnt信号通路的缺失与阿尔茨海默病（AD）的病理过程有关。从那时起，我们实验室和其他研究小组已经证实Wnt信号通路在AD的某些方面发挥作用。到目前为止，我们已经证明，通过使用糖原合酶激酶-3β（GSK-3β）抑制剂锂或不同的Wnt配体激活Wnt信号通路，可以保护神经元免受神经毒性损伤，包括β-淀粉样蛋白（Aβ）纤维和Aβ寡聚体。此外，我们发现一些激活知名神经递质系统和其他信号系统的分子，能够通过相互作用激活Wnt/β-连环蛋白信号通路，以保护神经元免受Aβ纤维或Aβ寡聚体的损伤。特别是，非经典Wnt信号通路的激活能够保护突触后区域和树突棘免受Aβ寡聚体的损伤。此外，Wnt信号配体还影响干细胞，它们也参与神经发生和胚胎发育过程中的细胞命运决定，以及神经系统中成年干细胞的分化。Wnt信号通路在调节它们的细胞分化或增殖状态中起关键作用。总之，这些在干细胞生物学和神经保护方面的发现，可能为神经退行性疾病的治疗引入新方法，包括药物筛选和针对激活Wnt信号通路的神经退行性疾病的治疗方法。
