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Whole Genome Expression Analysis in a Mouse Model of Tauopathy Identifies MECP2 as a Possible Regulator of Tau
Nicole M Maphis1, Shanya Jiang1, Jessica Binder1
1Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque NM, USA.
Abstract:
Increasing evidence suggests that hyperphosphorylation and aggregation of microtubule-associated protein tau (MAPT or tau) correlates with the development of cognitive impairment in Alzheimer's disease (AD) and related tauopathies. While numerous attempts have been made to model AD-relevant tau pathology in various animal models, there has been very limited success for these models to fully recapitulate the progression of disease as seen in human tauopathies. Here, we performed whole genome gene expression in a genomic mouse model of tauopathy that expressed human MAPT gene under the control of endogenous human MAPT promoter and also were complete knockout for endogenous mouse tau [referred to as 'hTau ' mice]. First, whole genome expression analysis revealed 64 genes, which were differentially expressed (32 up-regulated and 32 down-regulated) in the hippocampus of 6-month-old hTau mice compared to age-matched non-transgenic controls. Genes relevant to neuronal function or neurological disease include up-regulated genes: PKC-alpha (Prkca), MECP2 (Mecp2), STRN4 (Strn4), SLC40a1 (Slc40a1), POLD2 (Pold2), PCSK2 (Pcsk2), and down-regulated genes: KRT12 (Krt12), LASS1 (Cers1), PLAT (Plat), and NRXN1 (Nrxn1). Second, network analysis suggested anatomical structure development, cellular metabolic process, cell death, signal transduction, and stress response were significantly altered biological processes in the hTau mice as compared to age-matched non-transgenic controls. Further characterization of a sub-group of significantly altered genes revealed elevated phosphorylation of MECP2 (methyl-CpG-binding protein-2), which binds to methylated CpGs and associates with chromatin, in hTau mice compared to age-matched controls. Third, phoshpho-MECP2 was elevated in autopsy brain samples from human AD compared to healthy controls. Finally, siRNA-mediated knockdown of MECP2 in human tau expressing N2a cells resulted in a significant decrease in total and phosphorylated tau. Together, these results suggest that MECP2 is a potential novel regulator of tau pathology relevant to AD and tauopathies.
Insights
Methyl-CpG-binding protein-2 (MECP2) phosphorylation is elevated in Alzheimer's disease (AD) and tauopathy models. Reducing MECP2 levels decreases tau pathology, suggesting MECP2 is a novel regulator of tau in AD.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Microtubule-associated protein tau (MAPT) hyperphosphorylation and aggregation correlate with cognitive decline in Alzheimer's disease (AD) and tauopathies.
- Existing animal models often fail to fully replicate human tauopathy progression.
Purpose of the Study:
- To investigate gene expression changes in a novel human tau mouse model.
- To identify novel regulators of tau pathology relevant to AD and tauopathies.
Main Methods:
- Whole genome gene expression analysis in hTau mice (expressing human MAPT).
- Bioinformatic network analysis to identify altered biological processes.
- Western blot analysis to assess MECP2 phosphorylation in mouse and human brain samples.
- siRNA-mediated knockdown of MECP2 in cell culture.
Main Results:
- 64 differentially expressed genes identified in hTau mice hippocampus.
- Altered biological processes include anatomical development, metabolism, cell death, and stress response.
- Elevated phosphorylated MECP2 (phospho-MECP2) observed in hTau mice and human AD brains.
- MECP2 knockdown reduced total and phosphorylated tau levels in cells.
Conclusions:
- MECP2 is a potential novel regulator of tau pathology in AD and tauopathies.
- Elevated phospho-MECP2 may contribute to tauopathy progression.
- Targeting MECP2 could offer a therapeutic strategy for AD and related disorders.
