Research PaperSodium selenate activated Wnt/β-catenin signaling and repressed amyloid-β formation in a triple transgenic mouse model of Alzheimer's disease

- Selenate reduces phosphorylated APP to prevent APP processing and Aβ generation.
- Selenate activates Wnt/β-catenin pathway via PP2A activation.
- Activated Wnt/β-catenin pathway regulates the genes TXNRD2 and BACE1 transcription.
- Activated Wnt/β-catenin pathway blocks Aβ generation and neuronal apoptosis.

Accumulating evidences show that selenium dietary intake is inversely associated with the mortality of Alzheimer's disease (AD). Sodium selenate has been reported to reduce neurofibrillary tangles (NFT) in the tauopathic mouse models, but its effects on the Wnt/β-catenin signaling pathway and APP processing remain unknown during AD formation. In this paper, triple transgenic AD mice (3 × Tg-AD) had been treated with sodium selenate in drinking water for 10 month before the detection of hippocampal pathology. Increased Aβ generation, tau hyperphosphorylation and neuronal apoptosis were found in the hippocampus of AD model mouse. Down-regulation of Wnt/β-catenin signaling is closely associated with the alteration of AD pathology. Treatment with sodium selenate significantly promoted the activity of protein phosphatases of type 2A (PP2A) and repressed the hallmarks of AD. Activation of PP2A by sodium selenate could increase active β-catenin level and inhibit GSK3β activity in the hippocampal tissue and primarily cultured neurons of AD model mouse, leading to activation of Wnt/β-catenin signaling and transactivation of target genes, including positively-regulated genes c-myc, survivin, TXNRD2 and negatively-regulated gene BACE1. Meanwhile, APP phosphorylation was also reduced on the Thr668 residue after selenate treatment, causing the decreases of APP cleavage and Aβ generation. These findings reveal that the Wnt/β-catenin signaling is a potential target for prevention of AD and sodium selenate may be developed as a new drug for AD treatment.

Sodium selenate activates the Wnt/β-catenin signaling through PP2A to block the crosstalk among Aβ generation and neuronal apoptosis in the triple transgenic model mouse of AD.156