title: Life extension factor klotho prevents mortality and enhances cognition in hAPP transgenic mice.
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.
authors: Gladstone Institute of Neurological Disease, San Francisco, California 94158, Department of Neurology, University of California, San Francisco, California 94158, dena.dubal@ucsf.edu lmucke@gladstone.ucsf.edu.
authors: Dena B
authors: DB
authors: Dubal
authors: Gladstone Institute of Neurological Disease, San Francisco, California 94158, Department of Neurology, University of California, San Francisco, California 94158.
authors: Lei
authors: L
authors: Zhu
authors: Gladstone Institute of Neurological Disease, San Francisco, California 94158, Department of Neurology, University of California, San Francisco, California 94158.
authors: Pascal E
authors: PE
authors: Sanchez
authors: Gladstone Institute of Neurological Disease, San Francisco, California 94158, Department of Neurology, University of California, San Francisco, California 94158.
authors: Kurtresha
authors: http://orcid.org/0000-0001-5621-7979
authors: K
authors: Worden
authors: Department of Neurology, University of California, San Francisco, California 94158.
authors: Lauren
authors: L
authors: Broestl
authors: Gladstone Institute of Neurological Disease, San Francisco, California 94158, Department of Neurology, University of California, San Francisco, California 94158.
authors: Erik
authors: E
authors: Johnson
authors: Gladstone Institute of Neurological Disease, San Francisco, California 94158.
authors: Kaitlyn
authors: K
authors: Ho
authors: Gladstone Institute of Neurological Disease, San Francisco, California 94158.
authors: Gui-Qiu
authors: GQ
authors: Yu
authors: Gladstone Institute of Neurological Disease, San Francisco, California 94158.
authors: Daniel
authors: D
authors: Kim
authors: Department of Neurology, University of California, San Francisco, California 94158.
authors: Alexander
authors: A
authors: Betourne
authors: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors: Makoto
authors: M
authors: Kuro-O
authors: Departments of Neurosciences and Pathology, University of California, San Diego, San Diego, California 92093, and.
authors: Eliezer
authors: E
authors: Masliah
authors: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118.
authors: Carmela R
authors: CR
authors: Abraham
authors: Gladstone Institute of Neurological Disease, San Francisco, California 94158, Department of Neurology, University of California, San Francisco, California 94158, dena.dubal@ucsf.edu lmucke@gladstone.ucsf.edu.
authors: Lennart
authors: L
authors: Mucke
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D003071:Cognition / Q000502:physiology*; D003072:Cognition Disorders / Q000235:genetics / Q000523:psychology; D005966:Glucuronidase / Q000502:physiology*; D006801:Humans; D000090265:Klotho Proteins; D008136:Longevity / Q000235:genetics* / Q000502:physiology; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009415:Nerve Net / Q000473:pathology; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D013569:Synapses / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D016194:Receptors, N-Methyl-D-Aspartate; D016875:tau Proteins; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: Alzheimer's disease; NMDA receptors; aging; cognition; klotho; mice