Neuroprotective role of lactoferrin from foetus to old age

A recent publication[1] discusses the neuroprotective role of lactoferrin (Lf) during early brain development and damage across the lifespan.
Recent research suggests that early neuroprotective pathways modulated by Lf may prevent neurodegeneration through anti-inflammatory, antioxidant and immunomodulatory processes.
Thus, Lf may have the potential to support brain development and cognition through nutrition and prevent the development of neuropsychiatric disorders later in life.[1]

Neuroprotective role of Lf

Maternal infections, iron deficiency anaemia, placental insufficiency leading to fetal growth failure and sepsis, and necrotic enterocolitis are commonly seen in preterm births and contribute to the inflammatory challenges that fetuses face and are also risk factors for preterm birth. This results in damage to the central nervous system and poor neurodevelopmental outcomes. In addition, premature infants are additionally susceptible to brain damage due to the imbalance between the production and scavenging of oxidative species, as their antioxidant system is not yet fully developed.
Due to its anti-inflammatory, immunomodulatory, iron-binding and antioxidant properties, lactoferrin may be an excellent candidate to support neuroprotection.[1]
In a clinical trial in pregnant women with iron deficiency anaemia, administration of Lf was shown to significantly improve parameters of iron homeostasis and reduce inflammatory parameters in blood serum and cervicovaginal fluid. This, together with the prevention of further cervical shortening by Lf administration, had a prolonging effect on the duration of pregnancy and there was no preterm birth in this group of subjects despite the presence of risk factors in the women.[2]
In addition, there is preclinical evidence that Lf administration during pregnancy may also modulate the effects of inflammation on fetal brain development and thus be neuroprotective against early brain damage.[1]

Promoting role of Lf on brain development and cognition

The first two years of a child's life are crucial for brain development, as the brain reaches 80% of its adult weight during this period.[3]
In addition to a neuroprotective effect, studies also showed positive influences on brain development and cognition in infants and children.
LF contains the two molecules iron and sialic acid (Sia), which are crucial for the early neurological development and cognitive functions of young children.
Iron is an essential nutrient that plays a structural and functional role in enhancing cognitive and motor development.
Sia is an important monosaccharide for the synthesis of brain gangliosides and sialylated glycoproteins, which in turn are important for brain development and cognitive abilities.[3]
One of the neuroprotective mechanisms of action of Lf is the increase in brain-derived neurotrophic factor (BDNF), which has been demonstrated in animal model studies.3 BDNF has several important functional roles in neuronal transmission and plasticity. It is involved in the formation of memory and learning, the survival of neurons and the promotion of growth and differentiation of new neurons and synapses. It is possible that the Lf-induced increase in BDNF levels and the subsequent effect of BDNF on the signal transduction cascade is the underlying molecular mechanism that explains how lactoferrin enhances cognition and memory, as BDNF plays an important role in a variety of neuronal functions.[3]
For clinical relevance, animal studies in piglets suggest that lower concentrations of Lf are more likely to improve neuronal development and cognition, while higher doses are more neuroprotective.[4]
This is an exciting research avenue for future human clinical trials.

Influence on neurodegenerative diseases in old age

Although most Lf research focuses on the neonatal period due to the presence of Lf in breast milk, there is emerging evidence on the benefits of Lf in neurodegenerative diseases.
Lf can pass through the blood-brain axis via receptor-mediated transcytosis, which is why Lf can arrive directly in the brain and have a positive effect on brain maturation and protection. This is possible because some of the putative receptors of Lf, such as LDL receptor-related protein 1 (LRP 1) and Intelectin 1, are found in the brain endothelium.[1]
Lf appears to be physiologically increased in postmortem Alzheimer's brains and in APP transgenic mice (mouse model for Alzheimer's disease) around the amyloid deposits, but the purpose is still unclear. Amyloid deposits, also known as Alzheimer's plaques, are protein accumulations on nerve cells that disrupt the oxygen and energy supply of these cells and are considered a significant factor in the development of the disease.[1]
In a first pilot study with Alzheimer's patients, the intake of Lf was shown to modulate the p-Akt/PTEN signalling pathway, which is deregulated in this disease.
Lf showed a significant enhancing effect on antioxidant and anti-inflammatory markers, which are markedly reduced in Alzheimer's disease. Similarly, elevated serum markers such as amyloid ß, oxidative stress markers, inflammatory markers and others were significantly reduced by Lf intervention. The improvement in these serum markers was reflected in improved cognitive function in the patients. Therefore, the authors conclude from these results that Lf provides a possible protective mechanism in AD through its ability to attenuate the pathological cascade of AD and cognitive decline via modulation of the p-Akt/PTEN pathway, which influences key players in inflammation and oxidative stress.[5]
There are other exciting approaches from animal model studies, such as intranasal use, which has been shown to reduce ß-amyloid deposition and improve cognitive decline. The intranasal route is a relatively new and very interesting approach due to its increased and targeted availability in the central nervous system.[6]
Recently, Lf has also been discussed as a possible biomarker for the early diagnosis of neurodegenerative diseases, as it was discovered that salivary Lf was reduced in patients with Alzheimer's disease. The causal relationship between salivary Lf and Alzheimer's disease is not yet known.[7]
These new findings suggest that lactoferrin is a promising candidate to prevent the development of neurodegenerative diseases.[1]
However, research on this is still very young and the state of research so far is thin, so new findings are eagerly awaited.