Evidence indicates that cholesterol oxidation products, named oxysterols, contribute to Alzheimer’s disease (AD) pathogenesis through various mechanisms. In this regard, we recently demonstrated that several oxysterols progressively accumulate in AD brain as disease worsens. Astrocytes support neuronal functioning in many ways; evidence suggests that astrocyte reactivity is involved in AD pathogenesis since astrocytic inflammatory pathways are important mediators of changes in tau and synapse health. Yet the outcome of astrocyte activation is not completely clear. Two oxysterol mixtures were used, whose composition was based on our previous oxysterol quantification in mild (early AD) and severe AD (late AD) brain samples. Mouse derived primary cortical astrocytes and neurons were used as in vitro models. Preliminary results showed that both the oxysterol mixtures modulate astrocyte reactivity inducing the synthesis of Lipocalin-2 and SerpinA3N, both proteins identified as new potential reactive astrocyte markers. Alongside the increase in Lipocalin-2 and SerpinA3N synthesis, astrocytes showed a clear morphological change indicative of reactivity. Co-culture experiments showed a significant reduction of the post-synaptic marker PSD95 protein levels and a concurrent increase of cleaved caspase-3 protein levels in neurons, suggesting that oxysterols could also indirectly affect neuronal health acting on astrocytes.
Oxysterol brain levels and Alzheimer's disease: the impact on astrocyte reactivity and neuronal health
Staurenghi E;Testa G;Gamba P;Giannelli S;Leonarduzzi G
2019-01-01
Abstract
Evidence indicates that cholesterol oxidation products, named oxysterols, contribute to Alzheimer’s disease (AD) pathogenesis through various mechanisms. In this regard, we recently demonstrated that several oxysterols progressively accumulate in AD brain as disease worsens. Astrocytes support neuronal functioning in many ways; evidence suggests that astrocyte reactivity is involved in AD pathogenesis since astrocytic inflammatory pathways are important mediators of changes in tau and synapse health. Yet the outcome of astrocyte activation is not completely clear. Two oxysterol mixtures were used, whose composition was based on our previous oxysterol quantification in mild (early AD) and severe AD (late AD) brain samples. Mouse derived primary cortical astrocytes and neurons were used as in vitro models. Preliminary results showed that both the oxysterol mixtures modulate astrocyte reactivity inducing the synthesis of Lipocalin-2 and SerpinA3N, both proteins identified as new potential reactive astrocyte markers. Alongside the increase in Lipocalin-2 and SerpinA3N synthesis, astrocytes showed a clear morphological change indicative of reactivity. Co-culture experiments showed a significant reduction of the post-synaptic marker PSD95 protein levels and a concurrent increase of cleaved caspase-3 protein levels in neurons, suggesting that oxysterols could also indirectly affect neuronal health acting on astrocytes.
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