Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 31, Pages 13888-13893Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1009038107
Keywords
frontotemporal lobar degeneration; protein phosphatase 2A; neurofibrillary tangle; transgenic; treatment
Categories
Funding
- University of Sydney
- National Health and Medical Research Council
- Australian Research Council
- Diabetes Australia Research Trust
- J. O. and J. R. Wicking Trust
- Australian Government
- Wenkart Foundation
- GlaxoSmithKline
- Alzheimer's Australia
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Alzheimer's disease (AD) brains are characterized by amyloid-beta-containing plaques and hyperphosphorylated tau-containing neurofibrillary tangles (NFTs); however, in frontotemporal dementia, the tau pathology manifests in the absence of overt amyloid-beta plaques. Therapeutic strategies so far have primarily been targeting amyloid-beta, 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 a mediating 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.
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