Hyperphosphorylation of tau by GSK-3β in Alzheimer’s disease: The interaction of Aβ and sphingolipid mediators as a therapeutic target

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the extracellular deposits of β amyloid peptides (Aβ) in senile plaques, and intracellular aggregates of hyperphosphorylated tau in neurofibrillary tangles (NFT). Although accumulation of Aβ has been long considered a leading hypothesis in the disease pathology, it is increasingly evident that the role hyperphosphorylation of tau in destabilization of microtubule assembly and disturbance of axonal transport is equally detrimental in the neurodegenerative process. The main kinase involved in phosphorylation of tau is glycogen-synthase kinase 3-beta (GSK-3β). Intracellular accumulation of Aβ also likely induces increase in hyperphosphorylated tau by a mechanism dependent on GSK-3β. In addition, Aβ affects production of ceramides, the major sphingolipids in mammalian cells, by acting on sphingomyelinases, enzymes responsible for the catabolic formation of ceramides from the sphingomyelin. Generated ceramides in turn increase production of Aβ by acting on β-secretase, a key enzyme in the proteolytic processing of the amyloid precursor protein (APP), altogether leading to a ceramide-Aβ-hyperphosphorylated tau cascade that ends in neuronal death. Modulators and inhibitors acting on members of this devastating cascade are considered as potential targets for AD therapy. There is still no adequate treatment for AD patients. Novel therapeutic strategies increasingly consider the combination of multiple targets and interactions among the key members of implicated molecular pathways. This review summarizes recent findings and therapeutic perspectives in the pathology and treatment of AD, with the emphasis on the interplay between hyperphosphorylated tau, amyloid β, and sphingolipid mediators.

Anti-Oxidative, Anti-Inflammatory and Anti-Apoptotic Effects of Flavonols: Targeting Nrf2, NF-κB and p53 Pathways in Neurodegeneration

“…In another study, quercetin prevented the okadaic acid-induced increase in tau phosphorylation by inhibiting the Ca 2+ -calpain-p25-cdk5 pathway [215]. Together with GSK-3β, cdk5 is considered as one of the major tau kinases in AD [49]. Increased activation of cdk5 is associated with increased apoptosis in neuronal cells.…”

“…Additionally, OS is accompanied by increased activity of many kinases involved in tau phosphorylation, such as glycogen synthase kinase-3β (GSK-3β), cyclin-dependent kinase 5 (cdk5) and mitogen-activated protein kinases (MAPKs) JNK and p38, and reduced activity of tau-related phosphatases, particularly protein phosphatase 2A (PP2A). Ultimately, these OS-related changes in enzyme activity end in hyperphosphorylation of tau and impairment of tau function [9,46,49,50].…”

The interactions of p53 with tau and Aß as potential therapeutic targets for Alzheimer’s disease

“…By GSK-3, tau is phosphorylated at 42 residues (Martin et al, 2013). GSK-3β is able to promote formation of tangle-like filaments in cell-free systems, stimulate phosphorylation of tau in neuronal cell cultures and induce tau hyperphosphorylation and cognitive decline in animal models (Hooper et al, 2008;Lei et al, 2011;Jazvinšćak Jembrek et al, 2013). Presenilin 1, as a part of γ-secretase complex that operates the second cut of APP to produce Aβ, participates in the regulation of GSK-3-mediated tau phosphorylation by bringing tau and GSK-3β in close proximity.…”

“…A connection between soluble Aβ and tau protein phosphorylation is well documented in AD pathology. Accumulating evidence indicates that soluble Aβ induces tau phosphorylation (Jin et al, 2011;Bloom, 2014;Stancu et al, 2014;Nery et al, 2014), and GSK-3 is recognized as an important link between Aβ and tau pathologies ( Figure 2; Huang and Jiang, 2009;Jazvinšćak Jembrek et al, 2013). Accumulation of Aβ oligomers inhibits phosphatidylinositol-3-kinase (PI-3K) and…”

A Closer Look into the Role of Protein Tau in the Identification of Promising Therapeutic Targets for Alzheimer’s Disease

“…Table 1 highlights some major enzymes that cause tau phosphorylation at various Ser/Thr sites. In various animal models, GSK-3β has shown to stimulate phosphorylation of tau in neuronal cell cultures, promote the formation of tangle-like filaments, eventuate tau hyperphosphorylation, resulting in cognitive decline [ 36 , 37 , 38 ]. Presenilin 1—a γ-secretase complex modulates the regulation of tau phosphorylation mediated by GSK-3β.…”