A monomer induces phosphorylation of Tau at Ser-214 through 2AR-PKA-JNK signaling pathway

Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with synaptic dysfunction, pathological accumulation of beta-amyloid peptide 1-42 (A beta(1-42)), and neuronal loss. The self-association of A beta(1-42) monomers (A beta-M) into soluble oligomers seems to be crucial for the development of neurotoxicity. Previous publications have shown that A beta oligomers and dimers might play key roles in inducing AD. The role of A beta-M was rarely investigated and still unclear in AD. To understand the effects of A beta-M on neurons and other cell types in the brain could be the key to understand its function. In our study, we found that A beta-M expression slowly induced cell apoptosis within 48 hours after transfection, beta 2 adrenergic receptor (beta 2AR) interacted with A beta-M in the pull-down and the yeast two-hybrid assays, and A beta-M played a major role in inducing phosphorylation of Tau at Ser-214, c-Jun N-terminal kinase (JNK) at Thr-183/Tyr-185, p70 ribosomal protein S6 kinase (p70S6K) at Thr-389. We also discovered that beta 2AR, G protein-coupled receptor kinase 2 (GRK2), and protein kinase A (PKA) mediated the phosphorylation of Tau and JNK. A beta-M induced phosphorylation of Tau at Ser-214 through both beta 2AR-cAMP/PKA-JNK and beta 2AR-GRK signaling pathways. Mitogen-activated protein kinase kinase (MEK) mediated the phosphorylation of p70S6K induced by A beta-M.