The protective effect of lactoferrin on ventral mesencephalon neurons against MPP + is not connected with its iron binding ability.

Jun Wang,Huiying Liu,Mingxia Bi,Junxia Xie,Ning Song

doi:10.1038/srep10729

Abstract

Lactoferrin (Lf) can bind to lactoferrin receptor (LfR), leading to iron transport through the plasma membrane. Besides iron transportation, Lf also has antioxidant and anti-inflammatory properties. In the brain, Lf is only synthesized by activated microglia. LfR is present in blood vessels and nigral dopaminergic neurons. Both nigral iron accumulation and microglia activation is believed to be involved in Parkinson’s disease (PD), moreover, increased Lf and LfR in dopaminergic neurons were found in PD cases and MPTP-intoxicated mice. How iron influences microglia to release Lf? Does Lf tend to transport iron to dopaminergic neurons leading to cell death or to protect dopaminergic neuron from neurotoxin? In this study, we observed that iron increased Lf synthesis in activated microglia. In ventral mesencephalon neurons, both iron-free Lf (apo-Lf) and iron-saturated Lf (holo-Lf) exerted neuroprotective effects against MPP+ by mechanisms, believed to enhance the mitochondrial transmembrane potential, improve Cu/Zn-superoxide dismutase activity, increase Bcl-2 expression. Although apo-Lf but not holo-Lf chelated cellular iron, there was no difference between the two types of Lf in the neuroprotection. Our data indicate that iron overload increases the activated microglia releasing Lf. Lf plays protective role on ventral mesencephalon neurons against MPP+, which is iron-chelating independent.

Highlights

(LfR) has been shown to be present at the surface of different tissues and cell types, participating in Lf internalization by a receptor-mediated pathway
There are three questions need us to clarify: 1) Both iron and activated microglia were increased in substantia nigra (SN) of Parkinson’s disease (PD) patients, how iron influences the function of microglia to release Lf? 2) What is the role for the up-regulations of Lf and LfR on the dopaminergic neurons in PD, does the Lf tend to transport iron to dopaminergic neurons leading to cell death or to protect dopaminergic neuron from neurotoxin
We analyzed Lf mRNA levels with real-time PCR (Fig. 1B).Consistent with the Lf secretion in MPP+-activated microglia supernatant, Lf mRNA level was increased in MPP+-activated microglia, which was further enhanced by ferric ammonium citrate (FAC) pretreatment

Summary

Introduction

(LfR) has been shown to be present at the surface of different tissues and cell types, participating in Lf internalization by a receptor-mediated pathway. In the SN, LfR immunoreactivity was increased on both dopaminergic neurons and microvasculature in patients with PD compared to healthy control. This increase was highest in the most severely affected dopaminergic cell groups, suggesting a relationship between Lf/LfR increase and dopaminergic neurons degeneration. Apo-Lf is the main form that microglia released, we still want to know if the iron-saturated holo-Lf is harmful to the dopaminergic neurons?. The results show that iron overload can increase the activated microglia releasing Lf. Apo-Lf plays protective role on VM neurons against MPP+, even when Lf is iron-saturated as holo-Lf, it is still protective on VM neurons.

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Results

Conclusion