Tau Suppression in a Neurodegenerative Mouse Model Improves Memory Function

K. SantaCruz; J. Lewis; T. Spires; J. Paulson; L. Kotilinek; M. Ingelsson; A. Guimaraes; M. DeTure; M. Ramsden; E. McGowan; C. Forster; M. Yue; J. Orne; C. Janus; A. Mariash; M. Kuskowski; B. Hyman; M. Hutton; K. H. Ashe

doi:10.1126/science.1113694

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Tau Suppression in a Neurodegenerative Mouse Model Improves Memory Function

K. SantaCruz1,*,
J. Lewis5,*,
T. Spires6,*,
J. Paulson2,
L. Kotilinek2,
M. Ingelsson6,
A. Guimaraes2,
M. DeTure5,
M. Ramsden2,
E. McGowan5,
C. Forster1,
M. Yue5,
J. Orne6,
C. Janus5,
A. Mariash2,
M. Kuskowski7,
B. Hyman6,
M. Hutton5,
K. H. Ashe2,3,4,7,†

¹ Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
² Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
³ Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
⁴ Graduate Program in Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
⁵ Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA.
⁶ Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, USA.
⁷ Geriatric Research, Education, and Clinical Center (GRECC), Minneapolis VA Hospital, Minneapolis, MN 55417, USA.

↵† To whom correspondence should be addressed. E-mail: hsiao005{at}umn.edu

↵* These authors contributed equally to this work.

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Science 15 Jul 2005:
Vol. 309, Issue 5733, pp. 476-481
DOI: 10.1126/science.1113694

K. SantaCruz

1 Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.

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J. Lewis

5 Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA.

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T. Spires

6 Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, USA.

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J. Paulson

2 Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.

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L. Kotilinek

2 Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.

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M. Ingelsson

6 Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, USA.

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A. Guimaraes

2 Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.

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M. DeTure

5 Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA.

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M. Ramsden

2 Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.

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E. McGowan

5 Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA.

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C. Forster

1 Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.

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M. Yue

5 Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA.

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J. Orne

6 Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, USA.

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C. Janus

5 Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA.

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A. Mariash

2 Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.

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M. Kuskowski

7 Geriatric Research, Education, and Clinical Center (GRECC), Minneapolis VA Hospital, Minneapolis, MN 55417, USA.

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B. Hyman

6 Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, USA.

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M. Hutton

5 Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA.

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K. H. Ashe

2 Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.

3 Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA.

4 Graduate Program in Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA.

7 Geriatric Research, Education, and Clinical Center (GRECC), Minneapolis VA Hospital, Minneapolis, MN 55417, USA.

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For correspondence: hsiao005@umn.edu

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Abstract

Neurofibrillary tangles (NFTs) are the most common intraneuronal inclusion in the brains of patients with neurodegenerative diseases and have been implicated in mediating neuronal death and cognitive deficits. Here, we found that mice expressing a repressible human tau variant developed progressive age-related NFTs, neuronal loss, and behavioral impairments. After the suppression of transgenic tau, memory function recovered, and neuron numbers stabilized, but to our surprise, NFTs continued to accumulate. Thus, NFTs are not sufficient to cause cognitive decline or neuronal death in this model of tauopathy.

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Tau Suppression in a Neurodegenerative Mouse Model Improves Memory Function

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