Aims

To determine the physiological functions of human high-density lipoprotein (HDL) particles on human endothelial cells cultured alone or in context with other cells of the neurovascular unit.

Abstract Body

Aims: To determine the physiological functions of human high-density lipoprotein (HDL) particles on human endothelial cells cultured alone or in context with other cells of the neurovascular unit.

Methods: We used primary and human iPSC cells in standard monoculture and in a 3-dimensional bioengineered arterial model of the perfused human cerebrovasculature to study cerebral amyloid angiopathy (CAA) as measured by Aβ deposition and transport, and Aβ-induced endothelial inflammation measured by monocyte binding.

Results: HDL vascular Aβ accumulation independently of its principal binding protein, scavenger receptor (SR)-BI, in contrast to the SR-BI-dependent mechanism by which HDL prevents Aβ-induced vascular inflammation. HDL also reduces CAA through four mechanisms: i) altering Aβ binding to collagen-I, ii) forming a complex with Aβ that maintains its solubility, iii) diminishing collagen-I expression by smooth-muscle cells (SMC), and iv) attenuating Aβ uptake in SMC perhaps by reducing LRP1 expression. Finally, HDL particles enriched in apolipoprotein (apo)E appear to be the major drivers of these effects.

Conclusions: Circulating HDL, particularly HDL particles with apoE, may have beneficial effects on the cerebrovasculature, acting from the lumen to facilitate Ab egress from the brain and reduce cerebrovascular inflammation.

Methods

We used primary and human iPSC cells in standard monoculture and in a 3-dimensional bioengineered arterial model of the perfused human cerebrovasculature to study cerebral amyloid angiopathy (CAA) as measured by Aβ deposition and transport, and Aβ-induced endothelial inflammation measured by monocyte binding.

Results

HDL vascular Aβ accumulation independently of its principal binding protein, scavenger receptor (SR)-BI, in contrast to the SR-BI-dependent mechanism by which HDL prevents Aβ-induced vascular inflammation. HDL also reduces CAA through four mechanisms: i) altering Aβ binding to collagen-I, ii) forming a complex with Aβ that maintains its solubility, iii) diminishing collagen-I expression by smooth-muscle cells (SMC), and iv) attenuating Aβ uptake in SMC perhaps by reducing LRP1 expression. Finally, HDL particles enriched in apolipoprotein (apo)E appear to be the major drivers of these effects.

Conclusions

Circulating HDL, particularly HDL particles with apoE, may have beneficial effects on the cerebrovasculature, acting from the lumen to facilitate Aβ egress from the brain and reduce cerebrovascular inflammation.