Increased 4R-Tau Induces Pathological Changes in a Human-Tau Mouse Model

Kathleen M M. Schoch; Sarah L L. DeVos; Rebecca L L. Miller; Seung J J. Chun; Michaela Norrbom; David F F. Wozniak; Hana N N. Dawson; C.  Frank Bennett; Frank Rigo; Timothy M M. Miller

doi:10.1016/j.neuron.2016.04.042

Increased 4R-Tau Induces Pathological Changes in a Human-Tau Mouse Model

Kathleen M M. Schoch, Sarah L L. DeVos, Rebecca L L. Miller, Seung J J. Chun, Michaela Norrbom, David F F. Wozniak, Hana N N. Dawson, C. Frank Bennett, Frank Rigo, Timothy M M. Miller

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130 Scopus citations

Abstract

Pathological evidence for selective four-repeat (4R) tau deposition in certain dementias and exon 10-positioned MAPT mutations together suggest a 4R-specific role in causing disease. However, direct assessments of 4R toxicity have not yet been accomplished in vivo. Increasing 4R-tau expression without change to total tau in human tau-expressing mice induced more severe seizures and nesting behavior abnormality, increased tau phosphorylation, and produced a shift toward oligomeric tau. Exon 10 skipping could also be accomplished in vivo, providing support for a 4R-tau targeted approach to target 4R-tau toxicity and, in cases of primary MAPT mutation, eliminate the disease-causing mutation.

Original language	English
Pages (from-to)	941-947
Number of pages	7
Journal	Neuron
Volume	90
Issue number	5
DOIs	https://doi.org/10.1016/j.neuron.2016.04.042
State	Published - Jun 1 2016

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title = "Increased 4R-Tau Induces Pathological Changes in a Human-Tau Mouse Model",

abstract = "Pathological evidence for selective four-repeat (4R) tau deposition in certain dementias and exon 10-positioned MAPT mutations together suggest a 4R-specific role in causing disease. However, direct assessments of 4R toxicity have not yet been accomplished in vivo. Increasing 4R-tau expression without change to total tau in human tau-expressing mice induced more severe seizures and nesting behavior abnormality, increased tau phosphorylation, and produced a shift toward oligomeric tau. Exon 10 skipping could also be accomplished in vivo, providing support for a 4R-tau targeted approach to target 4R-tau toxicity and, in cases of primary MAPT mutation, eliminate the disease-causing mutation.",

author = "Schoch, {Kathleen M M.} and DeVos, {Sarah L L.} and Miller, {Rebecca L L.} and Chun, {Seung J J.} and Michaela Norrbom and Wozniak, {David F F.} and Dawson, {Hana N N.} and Bennett, {C. Frank} and Frank Rigo and Miller, {Timothy M M.}",

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T1 - Increased 4R-Tau Induces Pathological Changes in a Human-Tau Mouse Model

AU - Schoch, Kathleen M M.

AU - DeVos, Sarah L L.

AU - Miller, Rebecca L L.

AU - Chun, Seung J J.

AU - Norrbom, Michaela

AU - Wozniak, David F F.

AU - Dawson, Hana N N.

AU - Bennett, C. Frank

AU - Rigo, Frank

AU - Miller, Timothy M M.

PY - 2016/6/1

Y1 - 2016/6/1

N2 - Pathological evidence for selective four-repeat (4R) tau deposition in certain dementias and exon 10-positioned MAPT mutations together suggest a 4R-specific role in causing disease. However, direct assessments of 4R toxicity have not yet been accomplished in vivo. Increasing 4R-tau expression without change to total tau in human tau-expressing mice induced more severe seizures and nesting behavior abnormality, increased tau phosphorylation, and produced a shift toward oligomeric tau. Exon 10 skipping could also be accomplished in vivo, providing support for a 4R-tau targeted approach to target 4R-tau toxicity and, in cases of primary MAPT mutation, eliminate the disease-causing mutation.

AB - Pathological evidence for selective four-repeat (4R) tau deposition in certain dementias and exon 10-positioned MAPT mutations together suggest a 4R-specific role in causing disease. However, direct assessments of 4R toxicity have not yet been accomplished in vivo. Increasing 4R-tau expression without change to total tau in human tau-expressing mice induced more severe seizures and nesting behavior abnormality, increased tau phosphorylation, and produced a shift toward oligomeric tau. Exon 10 skipping could also be accomplished in vivo, providing support for a 4R-tau targeted approach to target 4R-tau toxicity and, in cases of primary MAPT mutation, eliminate the disease-causing mutation.

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DO - 10.1016/j.neuron.2016.04.042

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Increased 4R-Tau Induces Pathological Changes in a Human-Tau Mouse Model

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