Nicole M. Maphis, Shanya Jiang, Jessica Binder, Carrie Wright, Banu Gopalan, Bruce T. Lamb, Kiran Bhaskar
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 (MaptKO(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 hTau (MaptKO(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 hTau (MaptKO(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 hTau (MaptKO(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.
Pharmacology, Toxicology and Pharmaceutical Science
3
7%
Medicine and Dentistry
3
7%
Other
7
16%
Unknown
12
27%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 11. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 07 April 2017.
All research outputs
#2,841,998
of 22,961,203 outputs
Outputs from Frontiers in Molecular Neuroscience
#373
of 2,900 outputs
Outputs of similar age
#58,914
of 333,987 outputs
Outputs of similar age from Frontiers in Molecular Neuroscience
#19
of 108 outputs
Altmetric has tracked 22,961,203 research outputs across all sources so far. Compared to these this one has done well and is in the 87th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 2,900 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 5.7. This one has done well, scoring higher than 86% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 333,987 tracked outputs that were published within six weeks on either side of this one in any source. This one has done well, scoring higher than 82% of its contemporaries.
We're also able to compare this research output to 108 others from the same source and published within six weeks on either side of this one. This one has done well, scoring higher than 81% of its contemporaries.
