Life extension factor klotho prevents mortality and enhances cognition in hAPP transgenic mice

J Neurosci. 2015 Feb 11;35(6):2358-71. doi: 10.1523/JNEUROSCI.5791-12.2015.


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.

Keywords: Alzheimer's disease; NMDA receptors; aging; cognition; klotho; mice.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / physiology*
  • Animals
  • Behavior, Animal / physiology
  • Cognition / physiology*
  • Cognition Disorders / genetics
  • Cognition Disorders / psychology
  • Glucuronidase / physiology*
  • Humans
  • Klotho Proteins
  • Longevity / genetics*
  • Longevity / physiology
  • Maze Learning / physiology
  • Mice
  • Mice, Transgenic
  • Nerve Net / pathology
  • Receptors, N-Methyl-D-Aspartate / physiology
  • Synapses / pathology
  • tau Proteins / metabolism


  • Amyloid beta-Protein Precursor
  • Receptors, N-Methyl-D-Aspartate
  • tau Proteins
  • Glucuronidase
  • Klotho Proteins