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Abstract
The klotho gene family consists of α-, β-, and γ-Klotho, which encode type I single-pass transmembrane proteins with large extracellular domains. α-Klotho exists as a full-length membrane-bound and as a soluble form after cleavage of the extracellular domain. Due to gene splicing, a short extracellular Klotho form can be expressed and secreted. Inactivation of α-Klotho leads to a phenotype that resembles accelerated aging, as the expression level of the α-Klotho protein in the hippocampal formation of mice decreases with age. Here, we show that intrahippocampal viral expression of secreted human α-Klotho alters social behavior and memory formation. Interestingly, overexpression of secreted human α-Klotho in the CA1 changed the nest-building behavior and improved object recognition, object location and passive avoidance memory. Moreover, α-Klotho overexpression increased hippocampal synaptic transmission in response to standardized stimulation strengths, altered paired-pulse facilitation of synaptic transmission, and enhanced activity-dependent synaptic plasticity. These results indicate that memory formation benefits from an augmented level of secreted α-Klotho.
Highlights
IntroductionThe klotho gene family consists of α-, β-, and γ-Klotho, which encode type I single-pass transmembrane proteins that were originally described as co-receptors for endocrine fibroblast growth factors (Kuro-o et al, 1997; Ito et al, 2000; Kurosu et al, 2007; Fon Tacer et al, 2010). α-Klotho is a pleiotropic protein that has been found to delay aging and to enhance cognition in mice (Nagai et al, 2003; Kurosu et al, 2005; Dubal et al, 2014). α-Klotho encodes a type I transmembrane protein consisting of 1014 amino acid residues in mice and rats (Kuro-o et al, 1997; Shiraki-Iida et al, 1998) and 1012 amino acid residues in humans (Matsumura et al, 1998)
- These results indicate that memory formation benefits from an augmented level of secreted α-Klotho but that some aspects of social behavior were altered
The klotho gene family consists of α, β, and γ-Klotho, which encode type I single-pass transmembrane proteins that were originally described as co-receptors for endocrine fibroblast growth factors (Kuro-o et al, 1997; Ito et al, 2000; Kurosu et al, 2007; Fon Tacer et al, 2010). α-Klotho is a pleiotropic protein that has been found to delay aging and to enhance cognition in mice (Nagai et al, 2003; Kurosu et al, 2005; Dubal et al, 2014). α-Klotho encodes a type I transmembrane protein consisting of 1014 amino acid residues in mice and rats (Kuro-o et al, 1997; Shiraki-Iida et al, 1998) and 1012 amino acid residues in humans (Matsumura et al, 1998)
Summary
The klotho gene family consists of α-, β-, and γ-Klotho, which encode type I single-pass transmembrane proteins that were originally described as co-receptors for endocrine fibroblast growth factors (Kuro-o et al, 1997; Ito et al, 2000; Kurosu et al, 2007; Fon Tacer et al, 2010). α-Klotho is a pleiotropic protein that has been found to delay aging and to enhance cognition in mice (Nagai et al, 2003; Kurosu et al, 2005; Dubal et al, 2014). α-Klotho encodes a type I transmembrane protein consisting of 1014 amino acid residues in mice and rats (Kuro-o et al, 1997; Shiraki-Iida et al, 1998) and 1012 amino acid residues in humans (Matsumura et al, 1998). The klotho gene family consists of α-, β-, and γ-Klotho, which encode type I single-pass transmembrane proteins that were originally described as co-receptors for endocrine fibroblast growth factors (Kuro-o et al, 1997; Ito et al, 2000; Kurosu et al, 2007; Fon Tacer et al, 2010). Α-Klotho encodes a type I transmembrane protein consisting of 1014 amino acid residues in mice and rats (Kuro-o et al, 1997; Shiraki-Iida et al, 1998) and 1012 amino acid residues in humans (Matsumura et al, 1998). Since the secreted α-Klotho protein does not require cleavage, it can be secreted directly into the extracellular space, reaching the cerebrospinal fluid and blood serum (Matsumura et al, 1998). ADAM10 and ADAM17 have α-secretase activity that is responsible for the cleavage of the amyloid precursor protein (APP)
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