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

Overview

Journal J Neurosci

Specialty Neurology

Date 2015 Feb 13

PMID 25673831

Citations 106

Authors

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

Affiliations

Soon will be listed here.

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.

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