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 human MAPT gene under the control of endogenous human MAPT promoter 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.

Tau overexpression impairs neuronal endocytosis by decreasing the GTPase dynamin 1 through the miR‐132/MeCP2 pathway

“…Here, we found that tau overexpression led to the loss of miR‐132, while miR‐132 deficiency in mice led to increased tau expression, phosphorylation, and aggregation. Moreover, in the hTau mouse brain, the MeCP2 level is increased, and MeCP2 can regulate tau expression and phosphorylation and thus contribute to tauopathy in AD (Maphis et al, ). These studies strongly suggest a vicious cycle of miR‐132‐tau or tau‐miR‐132‐MeCP2‐tau abnormalities in the tauopathies.…”

In Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism

“…The reduction of CERS1 protein in the Atxn2-CAG100-KIN mouse was accompanied by a decrease of Cers1 mRNA and correlated with the mild deficiency of many ceramide species. CERS1 inactivity leads to preferential degeneration of cerebellar Purkinje neurons, and Cers1 mRNA downregulation was reported in tauopathies [142], so a pathogenic role of CERS1 deficiency in SCA2 is likely. Similarly, a deficiency of Smpd3 encoding nSMase2 as detected in the KIN nervous tissue was reported to cause TDP-43 neurotoxicity and tauopathy, while Ataxin-2 depletion protects against TDP-43 aggregation and tauopathies, so this dysregulation appears to be another pathogenic event with SCA2-typical features.…”

DNA methylation in the pathology of Alzheimer's disease: from gene to cognition

“…115,116 Recent studies on epigenetic modifications in AD animal models with Aβ and tau-related pathologies showed upregulated MeCP2 levels in the hippocampus. 117,118 Although an increased level of phosphorylated MeCP2 was simultaneously observed in these AD animals, the phosphorylated site was reported to be at Ser80, whereas pSer421 remained unchanged. 118 Hence, it is possible that Aβ and tau-related pathology work in concert to suppress Bdnf expression, which disrupts normal synaptic functions, resulting in synaptic impairment and neuronal loss.…”