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 language | English (US) |
|---|---|
| Article number | eaag0481 |
| Journal | Science Translational Medicine |
| Volume | 9 |
| Issue number | 374 |
| DOIs | |
| State | Published - Jan 25 2017 |
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ASJC Scopus subject areas
- Medicine(all)
Cite this
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 journal › Article
}
TY - JOUR
T1 - Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy
AU - DeVos, Sarah L.
AU - Miller, Rebecca L.
AU - Schoch, Kathleen M.
AU - Holmes, Brandon B.
AU - Kebodeaux, Carey S.
AU - Wegener, Amy J.
AU - Chen, Guo
AU - Shen, Tao
AU - Tran, Hien
AU - Nichols, Brandon
AU - Zanardi, Tom A.
AU - Kordasiewicz, Holly B.
AU - Swayze, Eric E.
AU - Bennett, C. Frank
AU - Diamond, Marc I.
AU - Miller, Timothy M.
PY - 2017/1/25
Y1 - 2017/1/25
N2 - 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
AB - 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
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UR - http://www.scopus.com/inward/citedby.url?scp=85011390798&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.aag0481
DO - 10.1126/scitranslmed.aag0481
M3 - Article
C2 - 28123067
AN - SCOPUS:85011390798
VL - 9
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 374
M1 - eaag0481
ER -