Aß monomer induces phosphorylation of Tau at Ser-214 through ß2AR-PKA-JNK signaling pathway.

ABSTRACT

Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with synaptic dysfunction, pathological accumulation of ß-amyloid peptide 1-42 (Aß1-42 ), and neuronal loss. The self-association of Aß1-42 monomers (Aß-M) into soluble oligomers seems to be crucial for the development of neurotoxicity. Previous publications have shown that Aß oligomers and dimers might play key roles in inducing AD. The role of Aß-M was rarely investigated and still unclear in AD. To understand the effects of Aß-M on neurons and other cell types in the brain could be the key to understand its function. In our study, we found that Aß-M expression slowly induced cell apoptosis within 48 hours after transfection, ß2 adrenergic receptor (ß2AR) interacted with Aß-M in the pull-down and the yeast two-hybrid assays, and Aß-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 ß2AR, G protein-coupled receptor kinase 2 (GRK2), and protein kinase A (PKA) mediated the phosphorylation of Tau and JNK. Aß-M induced phosphorylation of Tau at Ser-214 through both ß2AR-cAMP/PKA-JNK and ß2AR-GRK signaling pathways. Mitogen-activated protein kinase kinase (MEK) mediated the phosphorylation of p70S6K induced by Aß-M.