Oestrogens as modulators of neuronal signalosomes and brain lipid homeostasis related to protection against neurodegeneration.

Oestrogens trigger several pathways at the plasma membrane that exert beneficial actions against neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Part of these actions takes place in lipid rafts, which are membrane domains with a singular protein and lipid composition. These microdomains also represent a preferential site for signalling protein complexes, or signalosomes. A plausible hypothesis is that the dynamic interaction of signalosomes with different extracellular ligands may be at the basis of neuronal maintenance against different neuropathologies. Oestrogen receptors are localised in neuronal lipid rafts, taking part of macromolecular complexes together with a voltage-dependent anion channel (VDAC), and other molecules. Oestradiol binding to its receptor at this level enhances neuroprotection against amyloid-β degeneration through the activation of different signal transduction pathways, including VDAC gating modulation. Moreover, part of the stability and functionality of signalling platforms lays on the distribution of lipid hallmarks in these microstructures, which modulate membrane physicochemical properties, thus favouring molecular interactions. Interestingly, recent findings indicate a potential role of oestrogens in the preservation of neuronal membrane physiology related to lipid homeostasis. Thus, oestrogens and docosahexaenoic acid may act synergistically to stabilise brain lipid structure by regulating neuronal lipid biosynthetic pathways, suggesting that part of the neuroprotective effects elicited by oestrogens occur through mechanisms aimed at preserving lipid homeostasis. Overall, oestrogen mechanisms of neuroprotection may occur not only by its interaction with neuronal protein targets through nongenomic and genomic mechanisms, but also through its participation in membrane architecture stabilisation via 'lipostatic' mechanisms.