title: Whole Genome Expression Analysis in a Mouse Model of Tauopathy Identifies MECP2 as a Possible Regulator of Tau Pathology.
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 humanMAPTgene under the control of endogenous humanMAPTpromoter and also were complete knockout for endogenous mouse tau [referred to as 'hTauMaptKO(Duke)' 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 hTauMaptKO(Duke)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 hTauMaptKO(Duke)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 hTauMaptKO(Duke)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.
authors.affiliation: Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque NM, USA.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Maphis
authors.affiliation: Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque NM, USA.
authors.forename: Shanya
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque NM, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Binder
authors.affiliation: Lieber Institute for Brain Development, Baltimore MD, USA.
authors.forename: Carrie
authors.initials: C
authors.lastname: Wright
authors.affiliation: Department of Biostatistics, Cleveland Clinic Foundation Cleveland OH, USA.
authors.forename: Banu
authors.initials: B
authors.lastname: Gopalan
authors.affiliation: Stark Neurosciences Research Institute, Indiana University, Indianapolis IN, USA.
authors.forename: Bruce T
authors.initials: BT
authors.lastname: Lamb
authors.affiliation: Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque NM, USA.
authors.forename: Kiran
authors.initials: K
authors.lastname: Bhaskar
keywords: Alzheimer’s disease; MECP2; methyl-CpG-binding protein-2; microarray; tau protein; tau transgenic mice; tauopathies