Alpha-fetoprotein (AFP) modulates the effect of serum albumin on brain development by restraining the neurotrophic effect of oleic acid.

We have previously shown that serum albumin controls perinatal rat brain development through the regulation of oleic acid synthesis by astrocytes. In fact, oleic acid synthesized and released by astrocytes promoted neurite growth, neuron migration and the arrangement of prospective synapses. In this work we show that alpha-fetoprotein (AFP) is also present in the brain during embryonic development, its concentrations peaking at E15.

Oleic acid synthesized by stearoyl-CoA desaturase (SCD-1) in the lateral periventricular zone of the developing rat brain mediates neuronal growth, migration and the arrangement of prospective synapses.

Our previous work has shown that oleic acid synthesized by astrocytes in response to serum albumin behaves as a neurotrophic factor in neurons, upregulating the expression of GAP-43 and MAP-2 proteins, which are respectively markers of axonal and dendrite growth. In addition, oleic acid promoted neuron migration and aggregation, resulting in clusters of neurons connected each other by the newly formed neurites. In this work we show that the presence of albumin or albumin plus oleic acid increases neuron migration in cultured explants of the lateral periventricular zone, resulting in an increase in the number of GAP-43-positive neurons leaving the explant.

Oleic acid synthesized in the periventricular zone promotes axonogenesis in the striatum during brain development.

Our previous works showed that oleic acid synthesized in vitro by astrocytes in response to albumin behaves as a neurotrophic factor in neurons, up-regulating several proteins, such as the axonal growth marker growth-associated protein 43(GAP-43). Although the molecular mechanism of this process is fairly known, there is no evidence pinpointing the region/s in which oleic acid is synthesized. In this study, we show that the rate-limiting enzyme in oleic acid synthesis, stearoyl-CoA desaturase (SCD-1), is located in the periventricular zone of the brain of newborn rats, simultaneously to an increase in the amount of free oleic acid in the forebrain.

Albumin endocytosis via megalin in astrocytes is caveola- and Dab-1 dependent and is required for the synthesis of the neurotrophic factor oleic acid.

The synthesis and release of the neurotrophic factor oleic acid requires internalization of albumin into the astrocyte, which is mediated by megalin. In this study, we show that the binding and internalization of albumin involve its interaction with megalin, caveolin-1, caveolin-2 and cavin, but not with clathrin in astrocytes from primary culture. Electron microscopy analyses revealed albumin-gold complexes localized in caveolae, but not in clathrin-coated vesicles.

Megalin is a receptor for albumin in astrocytes and is required for the synthesis of the neurotrophic factor oleic acid.

We have previously shown that the uptake and transcytosis of albumin in astrocytes promote the synthesis of the neurotrophic factor oleic acid. Although the mechanism by which albumin induces oleic acid synthesis is well known, the mechanism of albumin uptake in astrocytes remains unknown. In this work, we found that astrocytes express megalin, an endocytic receptor for multiple ligands including albumin.