Cognition impairment in the genetic model of aging klotho gene mutant mice: a role of oxidative stress

Abstract

A new gene, termed klotho, is associated with the suppression of several aging phenotypes. Because high expression of klotho gene was detected in the brain, it would be plausible that klotho gene is involved in the regulation of brain aging. We investigated the changes in mnemonic function accompanying aging in klotho mutant mice. Cognitive function measured by novel-object recognition and conditioned-fear tests in klotho mutant mice was normal at the age of 6 wk, but markedly impaired at the age of 7 wk. Lipid (malondialdehyde) and DNA (8-hydroxy-2'-deoxyguanosine) peroxide levels in the hippocampus of klotho mutant mice increased at the age of 5 wk, 2 wk before the development of cognition deficits. Pro-death Bax increased, whereas anti-death Bcl-2 and Bcl-XL decreased, and apoptotic TUNEL-positive cells were detected in the hippocampus of klotho mutant mice at the age of 7 wk. A potent antioxidant, a-tocopherol, prevented cognition impairment and lipid peroxide accumulation and decreased the number of apoptotic cells in klotho mutant mice. These results suggest that oxidative stress has a crucial role in the aging-associated cognition impairment in klotho mutant mice. Klotho protein may be involved in the regulation of antioxidative defense.

The Allosteric Potentiation of Nicotinic Acetylcholine Receptors by Galantamine Ameliorates the Cognitive Dysfunction in Beta Amyloid25–35 I.c.v.-Injected Mice: Involvement of Dopaminergic Systems

“…The task was carried out on the days 6-8 after Ab 25À35 injection according to the protocol of Nagai et al (2003) and Kamei et al (2006) with a minor modification. The experimental apparatus consisted of a Plexiglas open-field box (40 Â 40 Â 29 (H) cm), the floor of which was covered with paper bedding (Japan SLC Inc., Shizuoka, Japan).…”

G-395A polymorphism in the promoter region of the KLOTHO gene associates with reduced cognitive impairment among the oldest old

“…A previous study found that KLOTHO mutant mice exhibited more impaired visual recognition and associative fear memory at 7 weeks than wild-type mice, whereas these animals displayed normal memory function at 6 weeks (Nagai et al 2003). Age-dependent memory impairment in KLOTHO gene mutant mice may result from age-associated oxidative neuronal membrane and DNA damage in the hippocampus (Nagai et al 2003). Recently, Dubal and colleagues conducted important studies of the Klotho gene and volume (Dubal et al 2014(Dubal et al , 2015Yokoyama et al 2015); these differences are mediated by mechanisms that involve the regulation of N-methyl-D-aspartate receptors and enriched synaptic GluN2B.…”

“…A previous study found that KLOTHO mutant mice exhibited more impaired visual recognition and associative fear memory at 7 weeks than wild-type mice, whereas these animals displayed normal memory function at 6 weeks (Nagai et al 2003). Age-dependent memory impairment in KLOTHO gene mutant mice may result from age-associated oxidative neuronal membrane and DNA damage in the hippocampus (Nagai et al 2003).…”

“…Although the KLOTHO gene was not associated with senile plaques, amyloid deposits, or other pathological brain changes (Kuro-o et al 1997;Shimokata et al 2006), it plays an increasingly important role in brain function with age in both mice and humans (Deary et al 2005;Nagai et al 2003;Shimokata et al 2006). A previous study found that KLOTHO mutant mice exhibited more impaired visual recognition and associative fear memory at 7 weeks than wild-type mice, whereas these animals displayed normal memory function at 6 weeks (Nagai et al 2003).…”

“…The relationship between the KLOTHO gene and cognitive impairment is an interesting line of research. A previous study found that KLOTHO-deficient mice exhibited memory impairment and hippocampal damage earlier than wildtype mice (Nagai et al 2003). Recent studies showed that the KLOTHO gene, KL-VS, is associated with improved cognition, and increases in klotho expression can decrease premature mortality and network dysfunction (key aspects of Alzheimer's disease) in human amyloid precursor protein transgenic mice (Dubal et al 2014(Dubal et al , 2015.…”