Cross talk between PI3K-AKT-GSK-3β and PP2A pathways determines tau hyperphosphorylation

Area of Science:

• Neuroscience
• Biochemistry
• Cell Biology

Background:

• Glycogen synthase kinase-3β (GSK-3β) and protein phosphatase 2A (PP2A) are key regulators of tau hyperphosphorylation.
• The intricate relationship and crosstalk between GSK-3β and PP2A in tau pathology remain incompletely understood.

Purpose of the Study:

• To elucidate the crosstalk between the PI3K-AKT-GSK-3β and PP2A signaling pathways.
• To determine the impact of this crosstalk on tau hyperphosphorylation and identify potential therapeutic targets.

Main Methods:

• Investigated the regulatory mechanisms of PP2A methylation and activity by GSK-3β.
• Examined the reciprocal regulation of GSK-3β phosphorylation and activity by PP2A.
• Analyzed the effects on tau phosphorylation at specific pathological sites.

Main Results:

• GSK-3β upregulates PP2A activity by increasing its methylation via suppression of protein phosphatase methylesterase-1 and phosphorylation of leucine carboxyl methyltransferase 1.
• PP2A downregulates GSK-3β activity by enhancing its Ser9 phosphorylation.
• Both enzymes mutually regulate each other, influencing tau phosphorylation directly and indirectly.

Conclusions:

• GSK-3β and PP2A exhibit reciprocal regulation, collectively controlling tau hyperphosphorylation.
• Inhibition of GSK-3β may be counteracted by PP2A inhibition, potentially exacerbating tau pathology.
• Targeting PP2A, which regulates tau phosphorylation at critical sites like Ser262/356, is proposed as a more effective strategy against tau pathology than targeting GSK-3β.