Abstract
Methyl-CpG-binding protein 2 (MECP2) is a critical transcriptional regulator for synaptic function. Dysfunction of synapses, as well as microglia-mediated neuroinflammation, represent the earliest pathological events in Alzheimer’s disease (AD). Here, expression, protein levels, and activity-related phosphorylation changes of MECP2 were analyzed in post-mortem human temporal cortex. The effects of wild type and phosphorylation-deficient MECP2 variants at serine 423 (S423) or S80 on microglial and neuronal function were assessed utilizing BV2 microglial monocultures and co-cultures with mouse cortical neurons under inflammatory stress conditions. MECP2 phosphorylation at the functionally relevant S423 site nominally decreased in the early stages of AD-related neurofibrillary pathology in the human temporal cortex. Overexpression of wild type MECP2 enhanced the pro-inflammatory response in BV2 cells upon treatment with lipopolysaccharide (LPS) and interferon-γ (IFNγ) and decreased BV2 cell phagocytic activity. The expression of the phosphorylation-deficient MECP2-S423A variant, but not S80A, further increased the pro-inflammatory response of BV2 cells. In neurons co-cultured with BV2 cells, the MECP2-S423A variant increased the expression of several genes, which are important for the maintenance and protection of neurons and synapses upon inflammatory stress. Collectively, functional analyses in different cellular models suggest that MECP2 may influence the inflammatory response in microglia independently of S423 and S80 phosphorylation, while the S423 phosphorylation might play a role in the activation of neuronal gene expression, which conveys neuroprotection under neuroinflammation-related stress.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia and one of the leading causes of cognitive disability worldwide
The brain samples were originally collected from individuals with a varying degree of AD-related neurofibrillary pathology according to Braak staging (0VI) [41]
Given the increasing evidence that Methyl-CpG-binding protein 2 (MECP2) is closely associated with microglial activation and synaptic dysfunction in pathophysiological conditions [8,9,10], we elucidated RNA, protein, and phosphorylation changes of MECP2 in this brain sample set
Summary
Alzheimer’s disease (AD) is the most common form of dementia and one of the leading causes of cognitive disability worldwide. Phosphorylation of mouse MECP2 at serine 421 (corresponding to S423 in human MECP2 isoform 1) upon neuronal activity has been shown to facilitate the release of a transcription factor from the MECP2 transcriptional repressor complex, coinciding with increased brain-derived neurotrophic factor (BDNF) expression, enhanced synaptic function, and improvement of learning and memory, but the role of these processes in the context of AD is not known [15]. Most of the studies addressing phosphorylation sites of MECP2 have focused on neurons To expand this view beyond neurons, we have here investigated the effects of elevated MECP2 isoform 1 levels in BV2 microglial cells upon LPS and IFNγ-induced inflammation. The expression of the MECP2 S423A variant in mouse primary cortical neurons co-cultured with BV2 microglial cells upon induction of inflammation led to expressional changes of several different transcripts that are important for neuronal and synaptic maintenance and protection, including Bdnf and Mapt, encoding tau protein. Our findings from neuron-BV2 co-cultures underline the important regulatory role of the S423 MECP2 phosphorylation site under neuroinflammation-related neuronal stress
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