Chronic Sodium Selenate Treatment Restores Deficits in Cognition and Synaptic Plasticity in a Murine Model of Tauopathy

Abstract

A major goal in diseases is identifying a potential therapeutic agent that is cost-effective and can remedy some, if not all, disease symptoms. In Alzheimer’s disease (AD), aggregation of hyperphosphorylated tau protein is one of the neuropathological hallmarks, and Tau pathology correlates better with cognitive impairments in AD patients than amyloid-β load, supporting a key role of tau-related mechanisms. Selenium is a non-metallic trace element that is incorporated in the brain into selenoproteins. Chronic treatment with sodium selenate, a non-toxic selenium compound, was recently reported to rescue behavioral phenotypes in tau mouse models. Here, we focused on the effects of chronic selenate application on synaptic transmission and synaptic plasticity in THY-Tau22 mice, a transgenic animal model of tauopathies. Three months with a supplement of sodium selenate in the drinking water (12 μg/ml) restored not only impaired neurocognitive functions but also rescued long-term depression (LTD), a major form of synaptic plasticity. Furthermore, selenate reduced the inactive demethylated catalytic subunit of protein phosphatase 2A (PP2A) in THY-Tau22 without affecting total PP2A.Our study provides evidence that chronic dietary selenate rescues functional synaptic deficits of tauopathy and identifies activation of PP2A as the putative mechanism.

A ß-Secretase Modulator Decreases Tau Pathology and Preserves Short-Term Memory in a Mouse Model of Neurofibrillary Degeneration

“…However, we noticed a sharp increase of PP2A C expression in the hippocampus of THY-Tau22 mice treated with PEL24-199 ( Figure 2E ). Methylation or demethylation of the catalytic subunit of PP2A C at leucine 309 residue reflects its phosphatase activity, where methylated PP2A c corresponds to the activated form of the phosphatase ( Papon et al, 2013 ; Sontag and Sontag 2014 ; Ahmed et al, 2020 ). The ratio of demethylated PP2A C showed no significant modification between untreated and treated animals, suggesting an unchanged activity ( Figure 2E ).…”

“…Modulation of tau phosphorylation can be attributed to the modification of PP2A expression, as there is an inverse relation between the hyperphosphorylation of tau Ser202/Thr205 and PP2A activity ( Kins et al, 2003 ). Moreover, increased activation of PP2A was shown to contribute to the restoration of cognitive functions in THY-Tau22 mice, also in a curative paradigm ( Ahmed et al, 2020 ). PP2A is inhibited in AD and suggested to contribute to the hyperphosphorylation of tau and the regulation of APP metabolism ( Taleski et al, 2021 ).…”

“Don’t Phos Over Tau”: recent developments in clinical biomarkers and therapies targeting tau phosphorylation in Alzheimer’s disease and other tauopathies

“…Sodium selenate has been identified as a potent activator of PP2A phosphatase enzymatic activity, leading to tau dephosphorylation [ 164 , 165 ]. In tau transgenic mouse models, oral treatment with sodium selenate reduces tau hyperphosphorylation, tau pathology progression, and behavioral and cognitive deficits [ 164 – 166 ]. By targeting tau phosphorylation in the early stages, it could be possible to slow or prevent the formation of tau inclusions.…”

Sodium selenate as a disease-modifying treatment for mild–moderate Alzheimer’s disease: an open-label extension study

“…4 5 Treatment with sodium selenate (VEL015) upregulates PP2A activity, and has been shown to reduce hyperphosphorylated tau levels in animal models of AD, epilepsy and traumatic brain injury. [6][7][8][9][10][11][12] In transgenic AD models, treatment with sodium selenate has repeatedly demonstrated reversal of cognitive deficits alongside reductions in tau and markers of neuroinflammation. 6 10-12 We have previously reported a phase 2a double-blind placebo-controlled randomised controlled trial (RCT) of sodium selenate (VEL015) in mild-moderate AD over 24 weeks.…”