Exploiting the neuroprotective effects of α-klotho to tackle ageing- and neurodegeneration-related cognitive dysfunction - PubMed (original) (raw)

Review

. 2021 Jun 14;5(2):NS20200101.

doi: 10.1042/NS20200101. eCollection 2021 Jun.

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Review

Exploiting the neuroprotective effects of α-klotho to tackle ageing- and neurodegeneration-related cognitive dysfunction

Kelsey Hanson et al. Neuronal Signal. 2021.

Abstract

Cognitive dysfunction is a key symptom of ageing and neurodegenerative disorders, such as Alzheimer's disease (AD). Strategies to enhance cognition would impact the quality of life for a significant proportion of the ageing population. The α-klotho protein may protect against cognitive decline through multiple mechanisms: such as promoting optimal synaptic function via activation of N-methyl-d-aspartate (NMDA) receptor signalling; stimulating the antioxidant defence system; reducing inflammation; promoting autophagy and enhancing clearance of amyloid-β. However, the molecular and cellular pathways by which α-klotho mediates these neuroprotective functions have yet to be fully elucidated. Key questions remain unanswered: which form of α-klotho (transmembrane, soluble or secreted) mediates its cognitive enhancing properties; what is the neuronal receptor for α-klotho and which signalling pathways are activated by α-klotho in the brain to enhance cognition; how does peripherally administered α-klotho mediate neuroprotection; and what is the molecular basis for the beneficial effect of the VS variant of α-klotho? In this review, we summarise the recent research on neuronal α-klotho and discuss how the neuroprotective properties of α-klotho could be exploited to tackle age- and neurodegeneration-associated cognitive dysfunction.

Keywords: Alzheimers disease; aging; cognition; neurodegeneration; neuroprotection.

© 2021 The Author(s).

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Conflict of interest statement

The authors declare that there are no competing interests associated with the manuscript.

Figures

Figure 1

Figure 1. The different forms of α-klotho

(A) The α-klotho gene produces a single pass type I transmembrane protein with a short intracellular domain (11 amino acids), a transmembrane domain (21 amino acids) and a large extracellular domain (980 amino acids). The extracellular domain contains two homologous repeats termed KL1 and KL2. The transmembrane form is shed from the membrane by the action of ADAM10/17 (α-cut), within the sequence LGSGTLGRF to produce soluble klotho. The second cleavage site (β-cut), also carried out by ADAM10/17, is between the KL1 and KL2 domains, within the sequence PPLPENQPL. The secreted form of klotho is produced by alternative splicing of the mRNA with a premature stop codon in exon 3, producing only the KL1 domain with an additional 15 amino acids at the C-terminus; with the sequence changing from DTTLSQFTDLNVYLW to SQLTKPISSLTKPYH. The secreted form is directly secreted from the cell. The klotho-VS polymorphism is located in the KL1 domain and is therefore present in all three forms of α-klotho. (B,C) HEK293 cells were stably transfected with the cDNAs encoding full-length transmembrane human klotho, soluble klotho or secreted klotho. Lysates (B) and media (C) were collected and immunoblotted with antibody LS-C500248. In the cell lysate full-length klotho migrates at 135 kDa, while in the media it migrates at 130 kDa due to its proteolytic shedding. The soluble and secreted forms of klotho migrate at 130 and 70 kDa, respectively, and are detected in both the cell lysate and media. In the media secreted klotho appears as two forms likely due to proteolytic processing.

Figure 2

Figure 2. Reported neuroprotective effects of klotho in cell culture and mouse models

Overview of the reported neuroprotective effects resulting from the overexpression of full-length or secreted klotho, or the administration of recombinant soluble klotho, in mouse models and administration of recombinant soluble klotho in cell culture models. See text for details including the uncertainty with several of the reported effects. Adapted from [23].

Figure 3

Figure 3. The muscarinic agonist carbachol promotes the shedding of klotho through activation of ADAM10

SH-SY5Y cells stably expressing klotho were incubated for 24 h with the muscarinic agonist carbachol (10 µM) and the selective ADAM10 inhibitor GI254023X (20 µM) as indicated. (A) Lysates and media were then prepared and immunoblotted for klotho with ab154163. (B) Quantitation of the amount of klotho in the media with the untreated cells set to 100%. Data are presented as mean ± SEM, _n_=4, Mann–Whitney test. * = P<0.05.

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