Ser423-phosphorylated MECP2 (MECP2-pS423) accumulates in human brain, cerebrospinal fluid and serum in sporadic Alzheimer's disease.

Methyl-CpG-binding protein 2 (MECP2) is a nuclear protein that serves as a global epigenetic repressor. Activity-dependent Ser421-phosphorylation is permissive to translocation of mouse Mecp2 to the cytoplasm, thereby reducing the repressor functions and activating neurotrophins. Mecp2-pS421 levels increase in neuron soma of AD (APP/PS1) mouse model and ablating Mecp2 increases activity of glycogen synthase kinase 3 beta, implying a link between MECP2 phosphorylation and Tau pathology in Alzheimer's disease (AD). It is currently unknown whether phosphorylation at the corresponding site of human MECP2-pS423 plays a role in AD. We developed an MECP2-pS423-specific antibody, and a quantitative selective reaction monitoring (SRM) assay based on LC-MS/MS analysis, and we used immunohistochemistry and proteomics to study MECP2-pS423 in human brain, cerebrospinal fluid (CSF), and serum specimens. In postmortem cortex and hippocampus, MECP2-pS423 expression increased across the clinicopathological spectrum of AD and correlated with histological progression and cognitive deficits. At the cellular level, MECP2-pS423 and pTau colocalized in granulovacuolar degeneration (GVD) bodies and neuritic plaques. Phosphoprotein levels of MECP2-pS423 increased in CSF and serum samples from patients clinically diagnosed as having AD premortem. Moreover, we found that a primate-specific and N-terminus truncated MECP2-E3 isoform mRNA was increased in postmortem middle temporal gyrus (MTG) of patients with AD. The results suggest that MECP2-pS423 is a promising mechanism-based biomarker and potential therapeutic target because its accumulations correlate with pathological and cognitive deficit in brain, CSF, and serum of human sporadic AD.