Francesca Zimetti (Italy)
University of Parma Department of Food and DrugAuthor Of 1 Presentation
O010 - PCSK9 modulates brain cholesterol metabolism and neuroinflammation in human cell models of astrocytes and neurons (ID 1140)
Abstract
Background and Aims
The Proprotein convertase subtilisin/kexin type 9 (PCSK9) seems to be involved in Alzheimer’s disease (AD) pathogenesis, although the mechanisms are still unknown. We investigated PCSK9 influence on cerebral lipid metabolism and neuroinflammation in human cell models of astrocytes and neurons.
Methods
The following models have been utilized: 1) human astrocytoma cells (U-373) exposed to human recombinant PCSK9; 2) human neuroblastoma cells (SH-SY5Y) overexpressing human PCSK9 and differentiated to neurons with retinoic acid.
Results
In U-373, exogenous PCSK9 reduced the expression of the LDL receptor (LDLr) and of the apoE receptor 2 (ApoER2); (-91 and -37%, respectively; p<0.05) and increased cholesterol synthesis (+44%; p<0.01), but the total cholesterol content was reduced (- 20%; p<0.05). In U373, PCSK9 did not affect plasma membrane cholesterol distribution nor efflux to isolated apoE or apoE-containing HDL. PCSK9 also worsened the inflammatory response induced by Aβ fibrils, further increasing the gene expression of IL-1β and TNF-α (p<0.05). In PCSK9-overexpressing SH-SY5Y, the uptake apoE-HDL-derived [3H]-cholesterol was significantly reduced compared to control cells (-30%; p<0.001). PCSK9 overexpression also reduced the interaction between fluorescein labelled-apoE and cells. Moreover, the expression of the ApoER2 and of the LDLr was significantly reduced (-33% and -57%, respectively; p<0.05). PCSK9 expression was associated to a reduced cell viability in Aβ fibrils-treated SH-SY5Y (-20%; p<0.05).
Conclusions
These results suggest a possible deleterious influence of PCSK9 on cerebral cholesterol metabolism and neuroinflammation. Ongoing studies will reveal whether the highlighted in vitro effects may lead to neurodegeneration in vivo, evaluating PCSK9 influence on cognitive function in AD animal models.
Presenter of 1 Presentation
O010 - PCSK9 modulates brain cholesterol metabolism and neuroinflammation in human cell models of astrocytes and neurons (ID 1140)
Abstract
Background and Aims
The Proprotein convertase subtilisin/kexin type 9 (PCSK9) seems to be involved in Alzheimer’s disease (AD) pathogenesis, although the mechanisms are still unknown. We investigated PCSK9 influence on cerebral lipid metabolism and neuroinflammation in human cell models of astrocytes and neurons.
Methods
The following models have been utilized: 1) human astrocytoma cells (U-373) exposed to human recombinant PCSK9; 2) human neuroblastoma cells (SH-SY5Y) overexpressing human PCSK9 and differentiated to neurons with retinoic acid.
Results
In U-373, exogenous PCSK9 reduced the expression of the LDL receptor (LDLr) and of the apoE receptor 2 (ApoER2); (-91 and -37%, respectively; p<0.05) and increased cholesterol synthesis (+44%; p<0.01), but the total cholesterol content was reduced (- 20%; p<0.05). In U373, PCSK9 did not affect plasma membrane cholesterol distribution nor efflux to isolated apoE or apoE-containing HDL. PCSK9 also worsened the inflammatory response induced by Aβ fibrils, further increasing the gene expression of IL-1β and TNF-α (p<0.05). In PCSK9-overexpressing SH-SY5Y, the uptake apoE-HDL-derived [3H]-cholesterol was significantly reduced compared to control cells (-30%; p<0.001). PCSK9 overexpression also reduced the interaction between fluorescein labelled-apoE and cells. Moreover, the expression of the ApoER2 and of the LDLr was significantly reduced (-33% and -57%, respectively; p<0.05). PCSK9 expression was associated to a reduced cell viability in Aβ fibrils-treated SH-SY5Y (-20%; p<0.05).
Conclusions
These results suggest a possible deleterious influence of PCSK9 on cerebral cholesterol metabolism and neuroinflammation. Ongoing studies will reveal whether the highlighted in vitro effects may lead to neurodegeneration in vivo, evaluating PCSK9 influence on cognitive function in AD animal models.