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Stemming the tide of tauopathy
Accumulation of the protein tau directly correlates with cognitive decline in Alzheimer’s disease and other primary tauopathies. One therapeutic option may be to reduce total tau. In a new study, DeVos et al. identified antisense oligonucleotides (ASOs) that decreased human tau in the brains of transgenic mice with tauopathy and observed the reversal of preexisting tau pathology and tau seeding activity. Further, neuronal loss was halted and mouse survival extended. In monkeys, tau ASOs reduced tau in the brain and cerebrospinal fluid. Together, these data support investigating lowering tau in human patients who have tau-positive inclusions even after pathological tau has begun to be deposited.
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.
- Copyright © 2017, American Association for the Advancement of Science
