Sodium selenate mitigates tau pathology, neurodegeneration, and functional deficits in Alzheimer's disease models

van Eersel, Janet, Ke, Yazi D., Liu, Xin, Delerue, Fabien, Kril, Jillian J., Gotz, Jürgen and Ittner, Lars M. (2010) Sodium selenate mitigates tau pathology, neurodegeneration, and functional deficits in Alzheimer's disease models. Proceedings of the National Academy of Sciences of the United States of America, 107 31: 13888-13893. doi:10.1073/pnas.1009038107


Author van Eersel, Janet
Ke, Yazi D.
Liu, Xin
Delerue, Fabien
Kril, Jillian J.
Gotz, Jürgen
Ittner, Lars M.
Title Sodium selenate mitigates tau pathology, neurodegeneration, and functional deficits in Alzheimer's disease models
Journal name Proceedings of the National Academy of Sciences of the United States of America   Check publisher's open access policy
ISSN 0027-8424
1091-6490
Publication date 2010-08-03
Sub-type Article (original research)
DOI 10.1073/pnas.1009038107
Open Access Status
Volume 107
Issue 31
Start page 13888
End page 13893
Total pages 6
Place of publication Washington, DC, United States
Publisher National Academy of Sciences
Language eng
Abstract Alzheimer's disease (AD) brains are characterized by amyloid-β- containing plaques and hyperphosphorylated tau-containing neurofibrillary tangles (NFTs); however, in frontotemporal dementia, the tau pathology manifests in the absence of overt amyloid-β plaques. Therapeutic strategies so far have primarily been targeting amyloid-β, although those targeting tau are only slowly beginning to emerge. Here, we identify sodium selenate as a compound that reduces tau phosphorylation both in vitro and in vivo. Importantly, chronic oral treatment of two independent tau transgenic mouse strains with NFT pathology, P301L mutant pR5 and K369I mutant K3 mice, reduces tau hyperphosphorylation and completely abrogates NFT formation. Furthermore, treatment improves contextual memory and motor performance, and prevents neurodegeneration. As hyperphosphorylation of tau precedes NFT formation, the effect of selenate on tau phosphorylation was assessed in more detail, a process regulated by both kinases and phosphatases. A major phosphatase implicated in tau dephosphorylation is the serine/threonine-specific protein phosphatase 2A (PP2A) that is reduced in both levels and activity in the AD brain. We found that selenate stabilizes PP2A-tau complexes. Moreover, there was an absence of therapeutic effects in sodium selenate-treated tau transgenic mice that coexpress a dominant-negative mutant form of PP2A, suggesting amediating role for PP2A. Taken together, sodium selenate mitigates tau pathology in several AD models, making it a promising lead compound for tau-targeted treatments of AD and related dementias.
Keyword Frontotemporal lobar degeneration
Neurofibrillary tangle
Protein phosphatase 2A
Transgenic
Treatment
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Queensland Brain Institute Publications
 
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