Ex vivo modulation of tau phosphorylation by hyperpolarized light: implications for Alzheimer’s disease therapy

Alzheimer’s disease (AD) is characterized by amyloid-β accumulation and tau hyperphosphorylation, leading to neurodegeneration and cognitive decline. Photobiomodulation (PBM) has shown promise in mitigating AD pathology, yet its effects on tau remain poorly understood. We investigated the impact of high-polarized light (HPL; Bioptron Quantum Hyperlight, 350–3400 nm) on tau phosphorylation using an ex vivo rat brain slice model of synthetic torpor (ST), a reversible hypometabolic state inducing controlled tau hyperphosphorylation. Slices were incubated at physiological (37 °C) or hypometabolic (25 °C) temperatures and exposed to HPL for 10 or 20 minutes. Western blot analyses of Tau-1 (non-phosphorylated tau), p-GSK3β (Ser9), and p-T205 revealed that HPL increased Tau-1 levels in warm slices, indicating a shift toward reduced tau hyperphosphorylation. p-GSK3β modulation was variable, reflecting inter-animal differences and temperature-dependent kinase/phosphatase dynamics. Cold slices exhibited smaller, more heterogeneous responses, consistent with suppressed metabolic activity and attenuated PBM signaling. Site-specific p-T205 changes suggest transient kinase activation and redox signaling, compatible with an overall trend toward normalized tau phosphorylation. These results highlight how HPL can modulate tau phosphorylation ex vivo, with the most consistent effects under normothermic conditions. Despite limitations, our findings provide preliminary evidence supporting HPL/PBM as a potential therapeutic strategy for tauopathies. Future in vivo studies are warranted to elucidate mechanisms, optimize dosing, and explore glymphatic-mediated clearance in PBM-treated brains. Keywords: photobiomodulation, hyperpolarized light, Alzheimer, hypothermia, synthetic torpor, tau hyperphosphorylation How to Cite this paper: Emiliana Piscitiello, Barbara Truglia, Sara Castria, Alessandra Occhinegro, Elisa De Angelis, Luca Alberti, Ludovico Taddei, Timna Hitrec, Roberto Amici, Jack A. Tuszynski, Marco Luppi (2025) Ex vivo modulation of tau phosphorylation by hyperpolarized light: implications for Alzheimer’s disease therapy, Journal of Multiscale Neuroscience 4(3), 244-256. DOI: https://doi.org/10.56280/1714956796 Author Affiliation: Emiliana Piscitiello 1University of Bologna, Department of Biomedical and Neuromotor Sciences, Bologna, Italy, 40127. Barbara Truglia University of Alberta, Faculty of Engineering, Department of Biomedical Engineering, Edmonton, Canada, T6G1H9. Sara Castria Politecnico di Torino, Faculty of Engineering, Department of Mechanical and Aerospace Engineering (DIMEAS), Turin, Italy, 10129. Alessandra Occhinegro University of Bologna, Department of Biomedical and Neuromotor Sciences, Bologna, Italy, 40127. Elisa De Angelis University of Bologna, Department of Biomedical and Neuromotor Sciences, Bologna, Italy, 40127. Luca Alberti University of Bologna, Department of Biomedical and Neuromotor Sciences, Bologna, Italy, 40127. Ludovico Taddei University of Bologna, Department of Biomedical and Neuromotor Sciences, Bologna, Italy, 40127. Timna Hitrec University of Bologna, Department of Biomedical and Neuromotor Sciences, Bologna, Italy, 40127. Roberto Amici University of Bologna, Department of Biomedical and Neuromotor Sciences, Bologna, Italy, 40127. Jack A. Tuszynski University of Alberta, Faculty of Science, Department of Physics, Edmonton, Canada, T6G2E1. Politecnico di Torino, Faculty of Engineering, Department of Mechanical and Aerospace Engineering (DIMEAS), Turin, Italy, 10129. Marco Luppi University of Bologna, Department of Biomedical and Neuromotor Sciences, Bologna, Italy, 40127. Received: 31 August 2025 Accepted: 29 September 2025 Online Published: 30 September 2025 Conflict of Interest The author declares no conflict of interest ​Copyright: © 2025 The Author(s). Published by Neural Press. This is an open access article distributed under the terms and conditions of the CC BY 4.0 license. ​Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, Neural Press™ or the editors, and the reviewers. Any product that may be evaluated in this article, or claim that made by its manufacturer, is not guaranteed or endorsed by the publisher