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

Research output: Contribution to journalArticle

79 Citations (Scopus)

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 taumRNA and protein inmice expressingmutant 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 taumRNA 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. 2017

Original languageEnglish (US)
Article numbereaag0481
JournalScience Translational Medicine
Volume9
Issue number374
DOIs
StatePublished - Jan 25 2017

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Tauopathies
Antisense Oligonucleotides
Spinal Cord
Pathology
Brain
Primates
Cerebrospinal Fluid
Alzheimer Disease
Proteins
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

DeVos, S. L., Miller, R. L., Schoch, K. M., Holmes, B. B., Kebodeaux, C. S., Wegener, A. J., ... Miller, T. M. (2017). Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Science Translational Medicine, 9(374), [eaag0481]. https://doi.org/10.1126/scitranslmed.aag0481

Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. / DeVos, Sarah L.; Miller, Rebecca L.; Schoch, Kathleen M.; Holmes, Brandon B.; Kebodeaux, Carey S.; Wegener, Amy J.; Chen, Guo; Shen, Tao; Tran, Hien; Nichols, Brandon; Zanardi, Tom A.; Kordasiewicz, Holly B.; Swayze, Eric E.; Bennett, C. Frank; Diamond, Marc I.; Miller, Timothy M.

In: Science Translational Medicine, Vol. 9, No. 374, eaag0481, 25.01.2017.

Research output: Contribution to journalArticle

DeVos, SL, Miller, RL, Schoch, KM, Holmes, BB, Kebodeaux, CS, Wegener, AJ, Chen, G, Shen, T, Tran, H, Nichols, B, Zanardi, TA, Kordasiewicz, HB, Swayze, EE, Bennett, CF, Diamond, MI & Miller, TM 2017, 'Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy', Science Translational Medicine, vol. 9, no. 374, eaag0481. https://doi.org/10.1126/scitranslmed.aag0481
DeVos, Sarah L. ; Miller, Rebecca L. ; Schoch, Kathleen M. ; Holmes, Brandon B. ; Kebodeaux, Carey S. ; Wegener, Amy J. ; Chen, Guo ; Shen, Tao ; Tran, Hien ; Nichols, Brandon ; Zanardi, Tom A. ; Kordasiewicz, Holly B. ; Swayze, Eric E. ; Bennett, C. Frank ; Diamond, Marc I. ; Miller, Timothy M. / Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. In: Science Translational Medicine. 2017 ; Vol. 9, No. 374.
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