Life Extension Factor Klotho Prevents Mortality and Enhances Cognition in hAPP Transgenic Mice
- Dena B. Dubal1,2,
- Lei Zhu1,2,
- Pascal E. Sanchez1,2,
- Kurtresha Worden1,2,
- Lauren Broestl2,
- Erik Johnson1,2,
- Kaitlyn Ho1,
- Gui-Qiu Yu1,
- Daniel Kim1,
- Alexander Betourne2,
- Makoto Kuro-o3,
- Eliezer Masliah4,
- Carmela R. Abraham5, and
- Lennart Mucke1,2
- 1Gladstone Institute of Neurological Disease, San Francisco, California 94158,
- 2Department of Neurology, University of California, San Francisco, California 94158,
- 3Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390,
- 4Departments of Neurosciences and Pathology, University of California, San Diego, San Diego, California 92093, and
- 5Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118
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Author contributions: D.B.D., C.R.A., and L.M. designed research; D.B.D., L.Z., P.E.S., K.W., L.B., E.J., K.H., G.-Q.Y., D.K., A.B., and E.M. performed research; D.B.D., M.K.-o., and L.M. contributed unpublished reagents/analytic tools; D.B.D., L.Z., P.E.S., K.W., L.B., E.J., G.-Q.Y., D.K., A.B., M.K.-o., E.M., and L.M. analyzed data; D.B.D. and L.M. wrote the paper.
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.
- Received December 18, 2012.
- Revision received December 6, 2014.
- Accepted December 21, 2014.
- Copyright © 2015 the authors 0270-6474/15/352358-14$15.00/0
