Iannotta, Lucia (2018) Brain-Derived Neurotrophic Factor influences cholesterol trafficking between astrocytes and neurons - Effects of Aging or a Fructose-rich diet on neurotrophin levels and markers of brain functioning. [Tesi di dottorato]

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Cholesterol is critical to maintain membrane plasticity, cellular function and synaptic integrity. The neurotrophin Brain-derived neurotrophic factor (BDNF) exerts a critical role in brain synaptic plasticity, learning and memory. It was previously reported that BDNF elicits cholesterol biosynthesis and promote the accumulation of presynaptic proteins in cholesterol-rich lipid rafts, but no further data are available on its ability to modulate physiological mechanisms involved in brain cholesterol homeostasis. One aim of this PhD research project was to investigate whether BDNF influences cholesterol homeostasis, focusing on the effect of the neurotrophin on Apolipoprotein E (ApoE) synthesis, cholesterol efflux from astrocytes and cholesterol incorporation into neurons. Our results show that BDNF significantly stimulates cholesterol efflux by astrocytes, as well as ATP binding cassette A1 (ABCA1) transporter and the expression of ApoE in cellular models of human astrocytes. On the other hand, BDNF reduce cholesterol incorporation in neurons by enhancing LXR-beta expression, protecting these cells from cholesterol excess-induced apoptosis. These results evidence a novel role of BDNF in the modulation of ApoE and cholesterol homeostasis in glial and neuronal cells. A further objective of this research project was to investigate the effects of a short-term (two-weeks) fructose-rich diet on brain redox homeostasis, autophagy, as well as on BDNF, its receptor TrkB and synaptic function markers, in the cortex of young and adults rats, in order to highlight the early risks to which brain is exposed. The results showed that a short-term fructose feeding was associated with an imbalance of redox homeostasis, as lower amount of Nuclear factor (erythroid derived 2)-like 2, lower activity of Glucose 6-phosphate dehydrogenase and Glutathione reductase, together with lower GSH/GSSG ratio, were found in fructose-fed young and adult rats. Fructose-rich diet was also associated with the activation of autophagy, as higher levels of Beclin, LC3 II and P62 were detected in cortex of fructose-fed rats. A diet-associated decrease of synaptophysin, synapsin I, and synaptotagmin I, suggests an impairment of synaptic transmission in fructose-fed young and adult rats. Interestingly, BDNF amount was significantly lower only in fructose-fed adult rats, while the level of its receptor TrkB decreased in both group of treated rats. A further marker of brain functioning, Acetylcholinesterase activity was found increased only in fructose-fed young animals. Overall, our findings suggest that young rats may severely suffer from the deleterious influence of fructose on brain health as the adults and provide experimental data suggesting the need of targeted nutritional strategies to reduce its amount in foods.

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