Klotho: relevance in the control of neuroinflammation in Parkinson’s disease

Abstract

Ageing is the primary risk factor for the development of Parkinson’s disease (PD), which is characterised by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta projecting to the striatum, leading to the depletion of striatal dopamine and, consequently, to the motor dysfunction typically observed. PD pathogenesis is not fully understood, but microglia-mediated neuroinflammation seems to contribute to dopaminergic neurodegeneration. Klotho is an anti-ageing protein that extends lifespan, protects hippocampal neurons and enhances cognition. It has anti-inflammatory properties in the kidney; however, there are no reports regarding this effect in the central nervous system, namely in the nigrostriatal pathway. Therefore, we obtained primary microglia cultures from the ventral midbrain and evaluated the effect of Klotho on LPS-induced microglial reactivity. The results showed that Klotho inhibits the LPS-induced iNOS expression, NO release and phagocytic activity. The receptors that may mediate Klotho’s anti-inflammatory effect are unknown and were further explored in this work. Finally, in order to evaluate the contribution of Klotho’s anti-inflammatory effect in its ability to protect dopaminergic neurons, we intended to eliminate microglia from a ventral midbrain neuron-glia mixed culture. However, microglia depletion was not effective which did not allow us to infer if Klotho’s anti-inflammatory effect contributes for its neuroprotective role. The results presented in this work show, for the first time, that Klotho is able to modulate microglial reactivity in the ventral midbrain, suggesting that it could be a potential therapeutic target for the control of neuroinflammation associated with PD.