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Articles, Neurobiology of Disease

Life Extension Factor Klotho Prevents Mortality and Enhances Cognition in hAPP Transgenic Mice

Dena B. Dubal, Lei Zhu, Pascal E. Sanchez, Kurtresha Worden, Lauren Broestl, Erik Johnson, Kaitlyn Ho, Gui-Qiu Yu, Daniel Kim, Alexander Betourne, Makoto Kuro-o, Eliezer Masliah, Carmela R. Abraham and Lennart Mucke
Journal of Neuroscience 11 February 2015, 35 (6) 2358-2371; DOI: https://doi.org/10.1523/JNEUROSCI.5791-12.2015
Dena B. Dubal
1Gladstone Institute of Neurological Disease, San Francisco, California 94158,
2Department of Neurology, University of California, San Francisco, California 94158,
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Lei Zhu
1Gladstone Institute of Neurological Disease, San Francisco, California 94158,
2Department of Neurology, University of California, San Francisco, California 94158,
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Pascal E. Sanchez
1Gladstone Institute of Neurological Disease, San Francisco, California 94158,
2Department of Neurology, University of California, San Francisco, California 94158,
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Kurtresha Worden
1Gladstone Institute of Neurological Disease, San Francisco, California 94158,
2Department of Neurology, University of California, San Francisco, California 94158,
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  • ORCID record for Kurtresha Worden
Lauren Broestl
2Department of Neurology, University of California, San Francisco, California 94158,
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Erik Johnson
1Gladstone Institute of Neurological Disease, San Francisco, California 94158,
2Department of Neurology, University of California, San Francisco, California 94158,
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Kaitlyn Ho
1Gladstone Institute of Neurological Disease, San Francisco, California 94158,
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Gui-Qiu Yu
1Gladstone Institute of Neurological Disease, San Francisco, California 94158,
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Daniel Kim
1Gladstone Institute of Neurological Disease, San Francisco, California 94158,
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Alexander Betourne
2Department of Neurology, University of California, San Francisco, California 94158,
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Makoto Kuro-o
3Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390,
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Eliezer Masliah
4Departments of Neurosciences and Pathology, University of California, San Diego, San Diego, California 92093, and
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Carmela R. Abraham
5Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118
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Lennart Mucke
1Gladstone Institute of Neurological Disease, San Francisco, California 94158,
2Department of Neurology, University of California, San Francisco, California 94158,
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Abstract

Aging is the principal demographic risk factor for Alzheimer disease (AD), the most common neurodegenerative disorder. Klotho is a key modulator of the aging process and, when overexpressed, extends mammalian lifespan, increases synaptic plasticity, and enhances cognition. Whether klotho can counteract deficits related to neurodegenerative diseases, such as AD, is unknown. Here we show that elevating klotho expression decreases premature mortality and network dysfunction in human amyloid precursor protein (hAPP) transgenic mice, which simulate key aspects of AD. Increasing klotho levels prevented depletion of NMDA receptor (NMDAR) subunits in the hippocampus and enhanced spatial learning and memory in hAPP mice. Klotho elevation in hAPP mice increased the abundance of the GluN2B subunit of NMDAR in postsynaptic densities and NMDAR-dependent long-term potentiation, which is critical for learning and memory. Thus, increasing wild-type klotho levels or activities improves synaptic and cognitive functions, and may be of therapeutic benefit in AD and other cognitive disorders.

  • aging
  • Alzheimer's disease
  • cognition
  • klotho
  • mice
  • NMDA receptors
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The Journal of Neuroscience: 35 (6)
Journal of Neuroscience
Vol. 35, Issue 6
11 Feb 2015
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Life Extension Factor Klotho Prevents Mortality and Enhances Cognition in hAPP Transgenic Mice
Dena B. Dubal, Lei Zhu, Pascal E. Sanchez, Kurtresha Worden, Lauren Broestl, Erik Johnson, Kaitlyn Ho, Gui-Qiu Yu, Daniel Kim, Alexander Betourne, Makoto Kuro-o, Eliezer Masliah, Carmela R. Abraham, Lennart Mucke
Journal of Neuroscience 11 February 2015, 35 (6) 2358-2371; DOI: 10.1523/JNEUROSCI.5791-12.2015

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Life Extension Factor Klotho Prevents Mortality and Enhances Cognition in hAPP Transgenic Mice
Dena B. Dubal, Lei Zhu, Pascal E. Sanchez, Kurtresha Worden, Lauren Broestl, Erik Johnson, Kaitlyn Ho, Gui-Qiu Yu, Daniel Kim, Alexander Betourne, Makoto Kuro-o, Eliezer Masliah, Carmela R. Abraham, Lennart Mucke
Journal of Neuroscience 11 February 2015, 35 (6) 2358-2371; DOI: 10.1523/JNEUROSCI.5791-12.2015
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Keywords

  • aging
  • Alzheimer's disease
  • cognition
  • klotho
  • mice
  • NMDA receptors

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