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

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

Kelsey Hanson 1, 

Kate Fisher 1 and 

Nigel M. Hooper1,2
1 Division of Neuroscience and Experimental Psychology, School of Biological Sciences,
Faculty of Biology, Medicine and Health, University of Manchester, M13 9PT, Manchester,
UK 

2 Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre,
Northern Care Alliance & University of Manchester, Manchester, UK
Correspondence: Kelsey Hanson (kelsey.hanson@manchester.ac.uk) or Nigel Hooper
(nigel.hooper@manchester.ac.uk)

Abstract

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

Introduction

Ageing is the primary risk factor for cognitive decline and most neurodegenerative disorders. Cognitive dysfunction is the major symptom of Alzheimer’s disease (AD), as well as being prominent in other forms of dementia. Thus, strategies to enhance cognition would impact on the quality of life for a significant proportion of the ageing population. α-klotho is a key antiageing gene: in mice its deficiency results in premature ageing and short life span [1], while its overexpression extends lifespan [2, 3]. In humans, a genetic variant of α-klotho is associated with enhanced cognition [3]. In mouse models, α-klotho protected against both age-associated decline in cognitive performance and neurodegenerative disease-associated cognitive dysfunction (reviewed in [4]). These observations have led to α-klotho being considered as a potential neuroprotective and cognitive-enhancing agent. However, the molecular and cellular mechanisms underpinning these observations are far from complete. The klotho family of genes includes α-klotho, β-klotho and γ-klotho [5], which are all translated as single-pass transmembrane proteins. α-klotho is highly expressed in the brain and kidney, and to a lesser extent in other organs [6]. In the periphery, transmembrane αklotho acts as a co-receptor for FGF23 to increase binding affinity to fibroblast growth factor (FGF) receptors. β-klotho is predominantly expressed in the liver, with lower levels present in the gut, kidney and spleen and mediates the activity of other members of the FGF family, mainly FGF-19 and FGF-21 [7, 8]. γ-klotho, whose function is ill-defined, is expressed in the kidney and skin [6, 7, 9]. In this review we outline the molecular and cellular properties of αklotho (referred to hereafter as klotho), its neuroprotective functions and the role of the VS variant in enhancing cognitive ability. In addition, we highlight critical gaps in our knowledge of the mechanisms by which klotho confers neuroprotection; gaps which if filled may open new therapeutic approaches to mimic klotho activity in age- and neurodegeneration associated cognitive dysfunction.