Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy
Sarah L DeVos, Rebecca L Miller, Kathleen M Schoch, Brandon B Holmes, Carey S Kebodeaux, Amy J Wegener, Guo Chen, Tao Shen, Hien Tran, Brandon Nichols, Tom A Zanardi, Holly B Kordasiewicz, Eric E Swayze, C Frank Bennett, Marc I Diamond, Timothy M Miller, Sarah L DeVos, Rebecca L Miller, Kathleen M Schoch, Brandon B Holmes, Carey S Kebodeaux, Amy J Wegener, Guo Chen, Tao Shen, Hien Tran, Brandon Nichols, Tom A Zanardi, Holly B Kordasiewicz, Eric E Swayze, C Frank Bennett, Marc I Diamond, Timothy M Miller
Abstract
Accumulation of hyperphosphorylated tau directly correlates with cognitive decline in Alzheimer's disease and other primary tauopathies. One therapeutic strategy may be to reduce total tau expression. We identified antisense oligonucleotides (ASOs) that selectively decreased human tau mRNA and protein in mice expressing mutant P301S human tau. After reduction of human tau in this mouse model of tauopathy, fewer tau inclusions developed, and preexisting phosphorylated tau and Thioflavin S pathology were reversed. The resolution of tau pathology was accompanied by the prevention of hippocampal volume loss, neuronal death, and nesting deficits. In addition, mouse survival was extended, and pathological tau seeding was reversed. In nonhuman primates, tau ASOs distributed throughout the brain and spinal cord and reduced tau mRNA and protein in the brain, spinal cord, and cerebrospinal fluid. These data support investigation of a tau-lowering therapy in human patients who have tau-positive inclusions even after pathological tau deposition has begun.
Conflict of interest statement
Competing interests: Both Ionis Pharmaceuticals and Washington University have filed for patents based on using Tau ASOs to treat CNS disorders (Patent#: PCT/US2013/031500; Date: 03/14/2013; Title: Methods for modulating Tau expression for reducing neurodegenerative syndromes; Co-inventors: S.L.D., C.F.B., T.M.M.; Patent#: 61/719,149; Date: 10/26/2012; Title: Methods for modulating Tau expression; Co-inventors: S.L.D., C.F.B, TMM). T.M.M. served on a medical advisory board for Ionis Pharmaceuticals and for Biogen Idec and is a consultant for Cytokinetics. The authors declare no other competing financial interests.
Copyright © 2017, American Association for the Advancement of Science.
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Source: PubMed