2. Academic Validation
  3. Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy

Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy

  • Sci Transl Med. 2017 Jan 25;9(374):eaag0481. doi: 10.1126/scitranslmed.aag0481.
Sarah L DeVos 1,  Rebecca L Miller 1,  Kathleen M Schoch 1,  Brandon B Holmes 1,  Carey S Kebodeaux 1,  Amy J Wegener 1,  Guo Chen 1,  Tao Shen 1,  Hien Tran 2,  Brandon Nichols 2,  Tom A Zanardi 2,  Holly B Kordasiewicz 2,  Eric E Swayze 2,  C Frank Bennett 2,  Marc I Diamond 3,  Timothy M Miller 4
Affiliations

Affiliations

  • 1 Department of Neurology, Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO 63110, USA.
  • 2 Ionis Pharmaceuticals, Carlsbad, CA 90201, USA.
  • 3 Center for Alzheimer's and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 4 Department of Neurology, Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO 63110, USA. miller.t@wustl.edu.
PMID: 28123067 DOI: 10.1126/scitranslmed.aag0481
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.

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