Sodium selenate mitigates tau pathology, neurodegeneration, and functional deficits in Alzheimer’s disease models
Open accessAbstract
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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Sodium selenate reduces tau protein phosphorylation by activating PP2A.
“Sodium selenate reduces tau protein phosphorylation by activating PP2A”
From Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review (2024) · cites this paper as [186]
Sodium selenate failed to produce improvements in cognition in a phase 2 clinical study.
“However, sodium selenate (selenate) failed to produce improvements in cognition in a phase 2 clinical study.”
From Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review (2024) · cites this paper as [186]
Due to insufficient clinical evidence, it cannot be assumed that enhancing phosphatase activity is beneficial in the treatment of AD.
“Due to insufficient clinical evidence, it cannot be assumed that enhancing phosphatase activity is beneficial in the treatment of AD [185,186].”
From Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review (2024) · cites this paper as [186]
Chronic low-dose sodium selenate reduced tau protein phosphorylation in cell culture and mouse disease models.
“Chronic low-dose sodium selenate reduced tau protein phosphorylation in cell culture and mouse disease models”
From Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review (2024) · cites this paper as [186]
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- Authors
- van Eersel, J., Ke, Y. D., Liu, X., Delerue, F., Kril, J. J., Götz, J., & Ittner, L. M.
- Affiliations
- Alzheimer's and Parkinson's Disease Laboratory, Brain and Mind Research Institute, University of Sydney, Camperdown, New South Wales 2050, Australia; and
- The University of Sydney (AU)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-07-19
- Volume
- 107
- Issue
- 31
- Pages
- 13888-13893
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2922247
- OpenAlex
- W2064038516
- Cited by
- 284
- References
- 55
- Citations by year
- 2026: 15 · 2025: 12 · 2024: 13 · 2023: 14 · 2022: 16 · 2021: 17 · 2020: 20 · 2019: 17 · 2018: 19 · 2017: 28 · 2016: 17 · 2015: 17 · 2014: 23 · 2013: 18 · 2012: 25
- FWCI
- 12.12
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- GlaxoSmithKline
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- sodium selenate, Alzheimer's disease, tau hyperphosphorylation, neurofibrillary tangles, protein phosphatase 2A, tau dephosphorylation, tau transgenic mice, memory impairment, motor performance, neurodegeneration, tau-targeted therapy, selenium
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, Memory, Mice, Transgenic, Mutation, Nerve Degeneration, Phosphorylation, Physical Conditioning, Animal, tau Proteins, Selenium Compounds, Cell Line, Tumor, Mice, Protein Phosphatase 2, Selenic Acid
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