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

TLDR

Alzheimer’s disease is marked by amyloid‑β plaques and hyperphosphorylated tau tangles, while tau pathology also appears in frontotemporal dementia; most therapies target amyloid‑β, and the phosphatase PP2A, which is diminished in AD, plays a key role in tau dephosphorylation. The study identifies sodium selenate as a compound that reduces tau phosphorylation in vitro and in vivo. The authors examined selenate’s impact on tau phosphorylation, a process governed by kinases and phosphatases, and found it to modulate this pathway. Chronic oral sodium selenate treatment in two tau‑transgenic mouse strains reduced hyperphosphorylated tau, eliminated NFT formation, improved memory and motor function, prevented neurodegeneration, stabilized PP2A‑tau complexes, and showed no benefit when PP2A was inhibited, demonstrating its potential as a tau‑targeted therapy for AD.

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 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.