Combination of PKCε Activation and PTP1B Inhibition Effectively Suppresses Aβ-Induced GSK-3β Activation and Tau Phosphorylation

Abstract

Glycogen synthase kinase-3β (GSK-3β) is a key element to phosphorylate tau and form neurofibrillary tangles (NFTs) found in tauopathies including Alzheimer's disease (AD). A current topic for AD therapy is focused upon how to prevent tau phosphorylation. In the present study, PKCε activated Akt and inactivated GSK-3β by directly interacting with each protein. Inhibition of protein tyrosine phosphatase 1B (PTP1B), alternatively, caused an enhancement in the tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1), allowing activation of Akt through a pathway along an IRS-1/phosphatidylinositol 3 kinase (PI3K)/3-phosphoinositide-dependent protein kinase-1 (PDK1)/Akt axis, to phosphorylate and inactivate GSK-3β. Combination of PKCε activation and PTP1B inhibition more sufficiently activated Akt and inactivated GSK-3β than each independent treatment, to suppress amyloid β (Aβ)-induced tau phosphorylation and ameliorate spatial learning and memory impairment in 5xFAD transgenic mice, an animal model of AD. This may represent an innovative strategy for AD therapy.

Linoleic Acid Derivative DCP-LA Prevents Tau Phosphorylation by Targeting GSK-3β

“…PKC activation or PTP1B inhibition is capable of inactivating GSK-3β each independently. In experiments using PC-12 cells, PKC overexpression and PTP1B deficiency activate Akt and inactivate GSK-3β synergistically [35]. This indicates that DCP-LA enables more efficient inactivation of GSK-3β by cooperation of PKC activation and PTP1B inhibition [35] (Figure 4).…”

“…The serine/threonine protein kinases such as PKC [35], Akt [35], PKA [36], integrin-linked kinase (ILK) [37], CaMKII [38], p90 ribosomal protein S6 kinase (p90RSK) [39], and cGMP-dependent protein kinase 1 (PrkG1) [40] inactivate GSK-3β by directly phosphorylating at Ser9 (Figure 1). Conversely, inhibition of those kinases allows relative activation of GSK-3β.…”

“…Akt1 is activated by being phosphorylated at Thr308 and Ser473 through the major pathway along a RTK/insulin receptor substrate 1 (IRS-1)/PI3K/3-phosphoinositide-dependent protein kinase 1 (PDK1)/Akt axis, to phosphorylate GSK-3β at Ser9 and inactivate GSK-3β [35] ( Figure 2). Accordingly, activation of RTK induces inactivation of GSK-3β; conversely, inhibition of RTK induces activation of GSK-3β.…”

“…PKC , activated by DCP-LA, inactivates GSK-3β by directly phosphorylating at Ser9 (Figure 4) [35]. Activated PKC , alternatively, activates Akt by directly phosphorylating at the serine residue, followed by inactivation of GSK-3β [35] (Figure 4).…”

“…Activated PKC , alternatively, activates Akt by directly phosphorylating at the serine residue, followed by inactivation of GSK-3β [35] (Figure 4). PKC activation or PTP1B inhibition is capable of inactivating GSK-3β each independently.…”