1 Introduction
α-Klotho protein gene was discovered randomly in 1997 by Kuro-o and colleagues (Kuro-o, Matsumura et al., 1997). The α- α-Klotho protein can be found in two forms, a transmembrane and a soluble one, the latter composed of both the cleaved α-Klotho and the secreted α-Klotho acting in the central nervous system (CNS) (Kuro-o, Matsumura et al., 1997; Ohyama, Kurabayashi et al., 1998; Wang & Sun, 2009). The transmembrane α-Klotho has a short intracellular domain and two extracellular domains, known as KL1 and KL2 and the secreted α-Klotho is a result of a alternative splicing composed of only KL1 (Kuro-o, Matsumura et al., 1997). These extracellular domains can be cleaved by the proteases disintegrin A and metalloproteinase 10 (ADAM10), disintegrin A and metalloproteinase 17 (ADAM17), and β-secretase 1 (BACE1). These cleavage fragments are present in the blood, urine, and cerebrospinal fluid acting as a humoral factor (Bloch, Sineshchekova et al., 2009; Chen, Podvin et al., 2007; Imura, Iwano et al., 2004).
Evidence suggest that α-Klotho expression is predominant circumscribed to the kidneys and the CNS (Kuro-o, Matsumura et al., 1997). This protein could be found in the choroid plexus (Nabeshima, 2002), in neurons, oligodendrocytes, in the cortical layers, in the hippocampal formation (Clinton, Glover et al., 2013), and Purkinje cells (German, Khobahy et al., 2012). The membrane-bound α-Klotho complexes with several fibroblast growth factor (FGF) receptors isoforms (Kuro-o, Matsumura et al., 1997), modulating kidney phosphate reabsorption and 1,25-dihidroxicholicalciferol (vitamin D) production for a systemic regulation of phosphate homeostasis (Erben, 2016; Razzaque, 2009). The soluble forms of α-Klotho act as a humoral factor and can be found in extracellular fluids such as blood, urine, and cerebral spinal fluid (CSF) (Akimoto, Yoshizawa et al., 2012; Imura, Iwano et al., 2004; Li, Watanabe et al., 2004).
Physiological and pathological processes influence the expression of α-Klotho. Rats with spontaneous hypertension, 5/6 nephrectomized, and type 1 diabetes had their α-Klotho mRNA levels decreased (Aizawa, Saito et al., 1998) and endogenous factors such as insulin and glutamate modulate α-Klotho expression in mouse neurons (Mazucanti, Kawamoto et al., 2019). The α-Klotho’s expression increases significantly after birth and adulthood (Clinton, Glover et al., 2013; Ohyama, Kurabayashi et al., 1998) and there is a decrease during aging (Duce, Podvin et al., 2008; King, Rosene et al., 2012; Xiao, Zhang et al., 2004).
In aging, there is a low-grade chronic systemic inflammation, called inflammaging (Franceschi, Bonafè et al., 2000). Deregulation of inflammation in the brain is associated not only with cognitive deficit related to aging (Ownby, 2010) but also in the pathogenesis and progression of neurodegenerative diseases (Kempuraj, Thangavel et al., 2016).
Lipopolysaccharides (LPS)-treated glial cells (a model of neuroinflammation) activates pathways involving TLR4 and the nuclear transcription factor kappa (NF-kB). The NF-κB activity plays an important role in modulating proteins and cytokines (Kinoshita, Yshii et al., 2017). This nuclear factor is constitutively expressed in the cytoplasm, where is binded to the inhibitor κB (IκB) protein which masks its nuclear localization signal, thus retaining it in the cytoplasm (Ghosh, May et al., 1998). Cytokines and other pro-inflammatory mediators are involved in hippocampal neuronal functions (Kim & Diamond, 2002), but they can also cause damage in hippocampal working memory consolidation and LTP (Kim & Diamond, 2002; Liu, Wu et al., 2012; Thomson & Sutherland, 2005). The present study investigated the role of α-Klotho and the activity of NF-kB in glial cells challenged with LPS and determine the ability of this protein to revert the neurotoxicity on neuronal culture cells caused by the GCM.