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.
Highlights
Tauopathies are a class of neurodegenerative diseases characterized by the accumulation of hyperphosphorylated, oligomeric and aggregated tau protein as neurofibrillary tangles (NFT) (Lee et al, 2001)
While Prkca was the only gene present in the overlapping region, Mecp2 was clearly unique to ‘neurological system process’ (Figure 2C). These results suggest that Prkca and Mecp2 are the most common genes relevant to several biological processes, which may have been altered in the hippocampus of hTauMaptKO(Duke) mice compared to with age-matched control (WT) controls
We report here on hTauMaptKO(Duke) mice as a novel humanized mouse model of tauopathy with complete deficiency of endogenous mouse Mapt
Summary
Tauopathies are a class of neurodegenerative diseases characterized by the accumulation of hyperphosphorylated, oligomeric and aggregated tau protein as NFTs (Lee et al, 2001). A growing number of studies implicate reasonably significant positive correlations between the build-up of NFTs and cognitive impairment in various tau-targeted imaging studies in humans (Nelson et al, 2012; Murray et al, 2015; Brier et al, 2016; Ossenkoppele et al, 2016; Scholl et al, 2016). It is still unclear how exactly hyperphosphorylated and/or aggregated tau contributes to neurodegenerative processes, numerous studies have suggested that tau-mediated pathological events occur either via loss-of-function or gain-of-toxic function with regards to microtubule interactions. Like Src/Fyn (Lee et al, 2004; Bhaskar et al, 2005; Vossel et al, 2010; Morris et al, 2011), somato-dendritic localization affecting synaptic function (Ittner et al, 2010; Ittner and Gotz, 2011), impairing neurogenesis (Komuro et al, 2015), neuron-to-neuron propagation and seeding of NFTs (Liu et al, 2012), as well as Abbreviations: ABC, avidin:biotinylated enzyme complex; AD, Alzheimer’s disease; ANOVA, analysis of variance; CBD, corticobasal degeneration; CpG, 5 -C—phosphate—G-3 (cytosine and guanine separated by only one phosphate); DAB, 3,3’-diaminobenzidine tetrahydrochloride; EGFP, enhanced green fluorescent protein; ETS, ETS proto-oncogene 1, transcription factor; FDR, false discovery rate; FN3K (Fn3k), fructosamine 3 kinase; FOXK2 (Foxk2), forkhead box K2; FTDP-17, fronto-temporal dementia and parkinsonism linked to chromosome 17; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GH (Gh or Gh1), growth hormone or growth hormone 1; GO, gene ontology; IF, immunofluorescence; IHC, immunohistochemistry; IPATM, Ingenuity Pathway Analysis; KRT12 (Krt12), type I intermediate filament chain keratin 12; LASS1 (Cers1), ceramide synthase 1; MAPT (Mapt), microtubule-associated protein tau; MECP2 (Mecp2), methyl-CpG-binding protein 2; MED7 (Med7), mediator complex subunit 7; NFT, neurofibrillary tangles; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells; NRXN1 (Nrxn1), neurexin 1; p-PKCα, phosphorylated PKCα; PBST, phosphate buffer saline with 0.1% tween; PCSK2 (Pcsk2), proprotein convertase subtilisin/kexin type 2; PiD, Pick’s disease; PKC (Prkca), protein kinase C alpha; pMECP2, phosphorylated MECP2; POLD2 (Pold2), polymerase (DNA) delta 2, accessory subunit; PSP, progressive supranuclear palsy; PXR, pregnane X receptor; QC, quality control; qRT-PCR, quantitative reverse transcription polymerase chain reaction; R-LIMMA, linear models for microarray and RNA-sequence; RAPGEFL1 (Rapgefl1), rap guanine nucleotide exchange factor like 1; RAR/RXR, retinoic acid receptors/retinoid receptor; SDS-PAGE, sodium dodecyl sulfate polyacrylamide gel electrophoresis; SFK, Src family kinase; SLC40a1 (Slc40a1), solute carrier family 40 member 1; STRN4 (Strn4), striatin 4; T-MECP2, total MECP2; T-PER, tissue protein extraction reagent; T-PKCα, total PKCα; TSC22D3 (Tsc22d3), TSC22 domain family member 3; VAT1L (Vat1l), vesicle amine transport 1-like; WDR18 (Wdr18), WD repeat domain 18; WG6, whole genome 6; WT, wild type; YBX3 (Ybx3), Y-box binding protein 3
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