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

Abstract

Glycogen synthase kinase GSK-3beta 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-3beta, have not been completely elucidated. GSK-3beta 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-3beta, 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-3beta 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.

The role of PI3K/AKT pathway and its therapeutic possibility in Alzheimer's disease

“…Based on our previous studies, the PI3K/AKT pathway is inhibited by Aβ and its recovery by diverse ways is helpful for the prevention of Aβ toxicity [14,15,54]. This finding is also supported by many other researchers [55][56][57]. In other words, Aβ oligomers inhibit the PI3K/AKT pathway and the inhibition of the PI3K/AKT pathway induces neuron death and eventually dementia.…”

Downregulation of canonical Wnt signaling in hippocampus of SAMP8 mice

“…Because inhibition of Wnt signaling by DKK-1 associates with increased GSK-3 activity and tau hyperphosphorylation (Caricasole et al, 2004;Mercado-Gómez et al, 2008;Rosi et al, 2010;SalcedoTello et al, 2014;Scali et al, 2006), we next studied whether this sequence of events would take place in our murine model. In agreement with this line, higher DKK-1 expression observed in the hippocampus of SAMP8 mice was accompanied by an increase in phosphorylated GSK-3a in Tyr 279 (active form), as well as a reduction of phosphorylated GSK-3b in Ser 9 (inactive form) protein levels.…”

Short-Term High-Fat-and-Fructose Feeding Produces Insulin Signaling Alterations Accompanied by Neurite and Synaptic Reduction and Astroglial Activation in the Rat Hippocampus

“…[21][22][23] It has also been proposed that insulin can modify microtubule stabilization through inhibition of glycogen synthase kinase 3b (GSK3b), a kinase that can phosphorylate the microtubule-associated protein (MAP) tau. 24,25 Given these crucial roles of insulin in the hippocampus, it could be speculated that systemic insulin alterations resulting from obesity and InsRes could result in hippocampal insulin alterations that underlie cognitive impairment. In this regard, it has been reported that long-term high-fat (not fructose) feeding in mice produced alterations in Akt and GSK3b signaling in the hippocampus.…”