2017
DOI: 10.1126/scitranslmed.aag0481
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Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy

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. Following reduction of human tau in this mouse model of tauopathy, fewer tau inclusions developed and pre-existing phosphorylated tau and thioflavin S pathology was reve… Show more

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Cited by 396 publications
(369 citation statements)
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References 71 publications
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“…We performed ICV injection of an ASO targeting human tau mRNA 10 in transgenic mice expressing the human tau transgene (hTau mice) to understand lowering of tau mRNA and total protein over time. To analyze newly generated hTau protein, we administered 13 C 6 ‐Leucine in the drinking water at designated time points (Fig.…”
Section: Resultsmentioning
confidence: 99%
See 3 more Smart Citations
“…We performed ICV injection of an ASO targeting human tau mRNA 10 in transgenic mice expressing the human tau transgene (hTau mice) to understand lowering of tau mRNA and total protein over time. To analyze newly generated hTau protein, we administered 13 C 6 ‐Leucine in the drinking water at designated time points (Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Previous data suggest this limitation may be due to the drug delivery paradigm in these experiments. The current study used a single bolus injection of ASO in rodent models while previous studies that observed total target protein lowering in CSF after ASO treatment in nonhuman primate models were performed with multiple intrathecal ASO injections 10, 21. Additionally, both transgenic animal models used here express wild‐type forms of the target protein.…”
Section: Discussionmentioning
confidence: 99%
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“…Inhibition of tau expression in animal models protects them from cognitive impairment (7,8), neuronal loss and reverses pathological tau deposition (38). The tau protein level is elevated 4 to 5-fold in AD brain (39,40), which may result from impaired degradation or/and overproduction of the protein.…”
Section: Discussionmentioning
confidence: 99%