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Inhibition of Wnt and PI3K Signaling Modulates GSK-3β Activity and Induces Morphological Changes in Cortical Neurons: Role of Tau Phosphorylation

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Abstract

Glycogen synthase kinase GSK-3β has been identified as one of the major candidates mediating tau hyperphosphorylation at the same sites as those present in tau protein in brain from Alzheimer′s disease (AD) patients. However, the signal transduction pathways involved in the abnormal activation of GSK-3β, have not been completely elucidated. GSK-3β activity is repressed by the canonical Wnt signaling pathway, but it is also modulated through the PI3K/Akt route. Recent studies have suggested that Wnt signaling might be involved in the pathophysiology of AD. On the other hand, modulators of the PI3K pathway might be reduced during aging leading to a sustained activation of GSK-3β, which in turn would increase the risk of tau hyperphosphorylation. The role of Wnt and PI3K signaling inhibition on the extent of tau phosphorylation and neuronal morphology has not been completely elucidated. Thus, in the present investigation we analyzed the effects of different negative modulators of the Wnt and the PI3K pathways on GSK-3β activation and phosphorylation of tau at the PHF-1 epitope in cortical cultured neurons and hippocampal slices from adult rat brain. Changes in the microtubule network were also studied. We found that a variety of Wnt and PI3K inhibitors, significantly increased tau phosphorylation at the PHF-1 site, induced the disarrangement of the microtubule network and the accumulation of tau within cell bodies. These changes correlated with alterations in neuronal morphology.

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Acknowledgements

The authors thank P. Davies for the generous gift of PHF-1 antibody and Patricia Ferrera for excellent technical assistance. This work was supported by CONACyT (48663), and DGAPA (IN217806) grants to C. Arias, CONACYT (48645-Q) grant to L. Massieu and CONACyT (42568-Q, and 53484) and DGAPA (IN200205), grants to J. Chimal. O. Mercado-Gómez was supported by 169933 CONACyT and DGEP (UNAM) fellowships, and K. Hernández-Fonseca by 167146 CONACyT and DGEP (UNAM) fellowships.

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Authors and Affiliations

  1. Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, P.O. Box AP 70-228, Mexico, DF, 04510, Mexico

    Octavio Mercado-Gómez, Alexa Villavicencio-Queijeiro, Jesús Chimal-Monroy & Clorinda Arias

  2. Departamento de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México AP 70-253, Mexico, DF, 04510, Mexico

    Karla Hernández-Fonseca & Lourdes Massieu

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  1. Octavio Mercado-Gómez
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  2. Karla Hernández-Fonseca
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Correspondence to Clorinda Arias.

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Special issue article in honor of Dr. Ricardo Tapia.

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Mercado-Gómez, O., Hernández-Fonseca, K., Villavicencio-Queijeiro, A. et al. Inhibition of Wnt and PI3K Signaling Modulates GSK-3β Activity and Induces Morphological Changes in Cortical Neurons: Role of Tau Phosphorylation. Neurochem Res 33, 1599–1609 (2008). https://doi.org/10.1007/s11064-008-9714-9

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