Therapeutic drugs modulate ATP-Binding cassette transporter-mediated transport of amyloid beta(1–42) in brain microvascular endothelial cells

Abstract

Deposition of amyloid-β peptide ) is a hallmark of Alzheimer's disease. Clearance of Aβ(1-42), across the blood-brain barrier (BBB), is mediated by ATP-binding Cassette (ABC) efflux transporters. Many therapeutic drugs inhibit ABC transporters, but little is known of the effect of therapeutic drugs on Aβ(1-42) transport across BBB endothelial cells.The effects of selected, widely prescribed, therapeutic drugs on ABCB1, ABCC5 and ABCG2 activities were determined by measuring intracellular levels of calcein, GS-MF, and Hoechst 33342 respectively in primary porcine brain endothelial cells (PBECs). The ability of ABCB1, ABCC5 and ABCG2 to transport Aβ(1-42) was determined using fluorescent Aβ(1-42).The ability of the ABCB1, ABCC5 and ABCG2 inhibitor telmisartan to modify transcellular Aβ(1-42) transport was investigated using PBEC monolayers housed in Transwell ® inserts.Treatment of PBECs with ABC transporter inhibitory drugs (indomethacin, olanzapine, chlorpromazine, telmisartan, pantoprazole, quinidine, sulfasalazine and nefazodone) increased Aβ(1-42) intracellular accumulation. Inhibition of ABCB1, ABCC5 and ABCG2 by telmisartan increased Aβ(1-42) transport in the apical to basal direction and reduced its transport in basal to apical direction in PBEC monolayers. ABCB1, ABCC5 and ABCG2 mediate the efflux transport of Aβ(1-42) in BBB endothelial cells. Inhibition of ABC transporters by therapeutic drugs, at plasma concentrations, could decrease Aβ(1-42) clearance from brain, across BBB endothelial cells into blood, and potentially influence levels of the Aβ(1-42) peptide within the brain.

Bisphenol A Inhibits the Transporter Function of the Blood-Brain Barrier by Directly Interacting with the ABC Transporter Breast Cancer Resistance Protein (BCRP)

“…62037-80-3; used as a replacement for perfluorooctanoic acid (PFOA) in consumer products, such as frying pans) have been shown to inhibit BCRP-mediated transport in rat brain capillaries [ 43 , 44 ]. In addition, many commonly used therapeutic drugs inhibit BCRP transporter activity [ 18 ]. Thus, as real-life exposure entails a combination of BPA and other chemicals affecting BCRP function, our findings are relevant for the general population.…”

“…For example, the BCRP seems to play an essential role in preventing blood-borne Aβ from entering the brain, as Abcg2 -knock out mice intravenously injected with Aβ display significantly more Aβ accumulation in their brains compared to WT mice [ 16 , 17 ]. Furthermore, in vitro studies have shown that the BCRP can transport Aβ out of brain endothelial cells [ 18 , 19 ].…”

Endothelial genetic deletion of CD147 induces changes in the dual function of the blood‐brain barrier and is implicated in Alzheimer’s disease

“… 9 , 10 , 13 In particular, ABCB1 expression decreases with age, 56 and it serves as an efflux pump reducing brain Aβ burden, 31 which is essential for CNS microenvironment equilibrium. 57 In addition, the coexpression of CD147 and ABCB1 has also been reported in prostate cancer, 55 which implies a potential relationship of these proteins in BECs. We analyzed the relevant DEGs regulated by CD147 and found that CD147 was correlated with several of these DEGs.…”

“…Other molecules used as transporters, such as TfR, Lrp, and FcRn, have been well studied 9,10,13 . In particular, ABCB1 expression decreases with age, 56 and it serves as an efflux pump reducing brain Aβ burden, 31 which is essential for CNS microenvironment equilibrium 57 . In addition, the coexpression of CD147 and ABCB1 has also been reported in prostate cancer, 55 which implies a potential relationship of these proteins in BECs.…”

Blood-Brain Barrier: More Contributor to Disruption of Central Nervous System Homeostasis Than Victim in Neurological Disorders

“…ABC transporters utilize ATP and pump out xenobiotics or endogenous metabolites to maintain EC homeostasis (Chow and Gu, 2015;De Rosa et al, 2015;Miller, 2015). ABCB1 (also known as P-glycoprotein, P-gp), ABCG2, and ABCC1 are all efflux transporters involved in the elimination of amyloid-β (Aβ), and so inhibition of these influences the Aβ level in the brain (Shubbar and Penny, 2020). In addition to AD, P-gp is involved in pathogenesis of stroke, epilepsy, and MS through upregulation or downregulation of expression influencing the inflammatory response (Huang et al, 2019).…”