Apolipoprotein A1 Enhances Endothelial Cell Survival in anIn VitroModel of ALS

Abstract

Altered lipoprotein metabolism is considered a pathogenic component of amyotrophic lateral sclerosis (ALS). Apolipoprotein A1 (ApoA1), a major high-density lipoprotein (HDL) protein, is associated with prevention of vascular damage. However, ApoA1’s effects on damaged endothelium in ALS are unknown. This study aimed to determine therapeutic potential of ApoA1 for endothelial cell (EC) repair under a pathologic condition reminiscent of ALS. We performed in vitro studies using mouse brain ECs (mBECs) exposed to plasma from symptomatic G93A SOD1 mice. Dosage effects of ApoA1, including inhibition of the phosphoinoside 3-kinase (PI3K)/Akt signaling pathway and integration of ApoA1 into mBECs were examined. Also, human bone marrow-derived endothelial progenitor cells (hBM-EPCs) and mBECs were co-cultured without cell contact to establish therapeutic mechanism of hBM-EPC transplantation. Results showed that ApoA1 significantly reduced mBEC death via the PI3K/Akt downstream signaling pathway. Also, ApoA1 was incorporated into mBECs as confirmed by blocked ApoA1 cellular integration. Co-culture system provided evidence that ApoA1 was secreted by hBM-EPCs and incorporated into injured mBECs. Thus, our study findings provide important evidence for ApoA1 as a potential novel therapeutic for endothelium protection in ALS. This in vitro study lays the groundwork for further in vivo research to fully determine therapeutic effects of ApoA1 in ALS.

Cellular and Noncellular Approaches for Repairing the Damaged Blood–CNS–Barrier in Amyotrophic Lateral Sclerosis

“…Notably, Garbuzova-Davis et al [ 89 ] investigated the therapeutic potential of ApoA1 on mBEC status in ALS-like conditions in vitro. The results showed that adding ApoA1 to culture media in a dose-dependent manner protected mBECs from cell injury induced by exposure to plasma from symptomatic G93A SOD1 mice.…”

“…The greatest reduction in cell death was found at ApoA1 concentration of 100 µg/mL. Also, co-culturing mBECs and hBMEPCs in ALS mouse plasma demonstrated that hBMEPCs secreted ApoA1, which integrated into mouse ECs via an activated PI3/Akt signaling pathway to exert beneficial effects [ 89 ]. These initial results suggest that ApoA1 is a promising agent for B-CNS-B repair, but the authors noted that ECs were cultured in fetal bovine serum, which may have influenced the lipid content of ECs.…”

“…These initial results suggest that ApoA1 is a promising agent for B-CNS-B repair, but the authors noted that ECs were cultured in fetal bovine serum, which may have influenced the lipid content of ECs. Further investigation into ApoA1’s mechanisms for repair could be conducted with ECs cultured in serum-free media to control this variable and determine the effects of ApoA1 on dysfunctional ECs [ 89 ]. Also, in vivo research on ApoA1’s actions at damaged CNS endothelium in ALS is needed to confirm whether the proposed treatment leads to B-CNS-B restoration.…”

A Current Update on the Role of HDL-Based Nanomedicine in Targeting Macrophages in Cardiovascular Disease

“…The structural properties of ApoA-I are harnessed in the synthesis of HDL nanotherapeutics as a naturally available blue print for design [ 75 , 76 ]. Apart from offering structural advantages to HDL nanoparticles as a scaffold for stability, HDL-associated ApoA-I is responsible for a majority of anti-inflammatory and atheroprotective properties of HDL, especially in promoting cholesterol efflux and preventing the migration of monocytes to the inflamed endothelia [ 77 , 78 , 79 , 80 , 81 ]. ApoA-I gene transfer in mice reduces TLR4 expression on the endothelial cells, which further regulates the expression of ICAM-1 and VCAM-1, hence controlling leucocyte migration across endothelia in response to inflammation [ 82 ].…”