lactoferrin and Nerve-Degeneration

Although Parkinson's disease is characterized by a loss of dopaminergic neurons in the substantia nigra not all dopaminergic neurons degenerate in this disease. This suggests that some specific factors make subpopulations of dopaminergic neurons more susceptible to the disease. Here, we show that the most vulnerable neurons are particularly sensitive to oxidative stress and rise in intracellular calcium concentrations. Because both events seem to occur in Parkinson's disease this may explain why some dopaminergic neurons degenerate and other do not.

Topics: Calcium; Calpain; Cell Death; Dopamine; Humans; Lactoferrin; Nerve Degeneration; Neurons; Oxidative Stress; Parkinson Disease; Substantia Nigra

Previous studies on postmortem human brain tissue have shown that the iron-binding glycoprotein lactoferrin is upregulated in dopamine (DA) neurons resistant to degeneration in Parkinson disease (PD). To study how this could possibly relate to disease progression, we used midbrain cultures and experimental settings that model the progressive loss of DA neurons in this disorder. Human lactoferrin of either recombinant or natural origin provided robust protection to vulnerable DA neurons in a culture paradigm in which these neurons die spontaneously and selectively as they mature. The efficacy of lactoferrin was comparable to that of glial cell line-derived neurotrophic factor, a prototypical neurotrophic factor for DA neurons. Neuroprotection by lactoferrin was attributable to its binding to heparan sulfate proteoglycans on the cell surface of DA neurons and subsequently to partial inactivation of focal adhesion kinase (FAK), a major effector kinase of integrins. We established that FAK inactivation served to unmask a prosurvival phosphoinositide 3-kinase/AKT-dependent signaling pathway that stimulates calcium shuttling from endoplasmic reticulum to mitochondria. DA neurons exposed to the mitochondrial toxin 1-methyl-4-phenylpyridinium were also partially protected by lactoferrin, further supporting the view that mitochondria may represent a downstream target for lactoferrin protective actions. Finally, we found that the iron binding capability of lactoferrin intervened in DA cell rescue only when neurodegeneration was consecutive to iron-catalyzed oxidative stress. Overall, our data suggest that the accumulation of lactoferrin in PD brains might be evidence of an attempt by the brain to minimize the consequences of neurodegeneration.

Topics: 1-Methyl-4-phenylpyridinium; Animals; Binding Sites; Calcium; Cell Death; Cells, Cultured; Dopamine; Focal Adhesion Kinase 1; Glial Cell Line-Derived Neurotrophic Factor; Homeostasis; Humans; Lactoferrin; Mesencephalon; Mitochondria; Nerve Degeneration; Neuroglia; Neurons; Parkinson Disease; Phosphatidylinositol 3-Kinases; Rats; Rats, Wistar; Recombinant Proteins

Lactotransferrin is a glycoprotein that specifically binds and transports iron. This protein is also believed to transport other metals such as aluminum. Several lines of evidence indicate that iron and aluminum are involved in the pathogenesis of many dementing diseases. In this context, the analysis of the iron-binding protein distribution in the brains of patients affected by neurodegenerative disorders is of particular interest. In the present study, the distribution of lactotransferrin was analyzed by immunohistochemistry in the cerebral cortex from patients presenting with Alzheimer's disease, Down syndrome, amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam, sporadic amyotrophic lateral sclerosis, or Pick's disease. The results show that lactotransferrin accumulates in the characteristic lesions of the different pathologic conditions investigated. For instance, in Alzheimer's disease and Guamanian cases, a subpopulation of neurofibrillary tangles was intensely labeled in the hippocampal formation and inferior temporal cortex. Senile plaques and Pick bodies were also consistently labeled. These staining patterns were comparable to those obtained with antibodies to the microtubule-associated protein tau and the amyloid beta A4 protein, although generally fewer neurofibrillary tangles were positive for lactotransferrin than for tau protein. Neuronal cytoplasmic staining with lactotransferrin antibodies, was observed in a subpopulation of pyramidal neurons in normal aging, and was more pronounced in Alzheimer's disease, Guamanian cases, Pick's disease, and particularly in Down syndrome. Lactotransferrin was also strongly associated with Betz cells and other motoneurons in the primary motor cortex of control, Alzheimer's disease, Down syndrome, Guamanian and Pick's disease cases. These same lactotransferrin-immunoreactive motoneurons were severely affected in the cases with amyotrophic lateral sclerosis. It is possible that in these neurodegenerative disorders affected neurons either take up or synthesize lactotransferrin to an abnormally elevated rate. An excessive accumulation of lactotransferrin, as well as transported iron and aluminum, may lead to a cytotoxic effect resulting in the formation of intracellular lesions and neuronal death.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyotrophic Lateral Sclerosis; Dementia; Down Syndrome; Female; Humans; Immunohistochemistry; Lactoferrin; Male; Middle Aged; Nerve Degeneration