Selenoprotein S Reduces Endoplasmic Reticulum Stress-Induced Phosphorylation of Tau: Potential Role in Selenate Mitigation of Tau Pathology

Article type: Research Article

Authors: Rueli, Rachel H.L.H.^a | Torres, Daniel J.^a | Dewing, Andrea S.T.^a | Kiyohara, Arlene C.^a | Barayuga, Stephanie M.^a | Bellinger, Miyoko T.^a | Uyehara-Lock, Jane H.^b | White, Lon R.^c | Moreira, Paula I.^d | Berry, Marla J.^a | Perry, George^e | Bellinger, Frederick P.^{a; *}

Affiliations: [a] Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawai’i at Manoa, Honolulu, HI, USA | [b] Department of Pathology, John A. Burns School of Medicine, University of Hawai’i at Manoa, Honolulu, HI, USA | [c] Pacific Health Research and Education Institute, Honolulu, HI, USA | [d] Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra and Faculty of Medicine, University of Coimbra, Coimbra, Portugal | [e] UTSA Neurosciences Institute and Department of Biology, University of Texas at San Antonio, San Antonio, TX, USA

Correspondence: [*] Correspondence to: Frederick P. Bellinger, Department of Cell and Molecular Biology, University of Hawai’i, 651 Ilalo Street, Honolulu, HI 96813, USA. Tel.: +1 808 692 1512; Fax: +1 808 692 1970; E-mail: [email protected].

Abstract: Previous studies demonstrated that selenium in the form of sodium selenate reduces neurofibrillary tangle formation in Alzheimer’s disease models. Hyperphosphorylation of tau, which leads to formation of neurofibrillary tangles in Alzheimer’s disease, is increased by endoplasmic reticulum (ER) stress. Selenoprotein S (SelS) is part of an ER membrane complex that removes misfolded proteins from the ER as a means to reduce ER stress. Selenate, as with other forms of selenium, will increase selenoprotein expression. We therefore proposed that increased SelS expression by selenate would contribute to the beneficial actions of selenate in Alzheimer’s disease. SelS expression increased with ER stress and decreased under conditions of elevated glucose concentrations in the SH-SY5Y neuronal cell line. Reducing expression of SelS with siRNA promoted cell death in response to ER stress. Selenate increased SelS expression, which significantly correlated with decreased tau phosphorylation. Restricting SelS expression during ER stress conditions increased tau phosphorylation, and also promoted aggregation of phosphorylated tau in neurites and soma. In human postmortem brain, SelS expression coincided with neurofibrillary tangles, but not with amyloid-β plaques. These results indicate that selenate can alter phosphorylation of tau by increasing expression of SelS in Alzheimer’s disease and potentially other neurodegenerative disorders.

Keywords: Alzheimer’s disease, endoplasmic reticulum stress, neurofibrillary tangle, selenium, selenoprotein, tau

DOI: 10.3233/JAD-151208

Journal: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 749-762, 2017