New Evidence for P-gp-Mediated Export of Amyloid-β PEPTIDES in Molecular, Blood-Brain Barrier and Neuronal Models

• Published in: International journal of molecular sciences 2020-12, Vol.22 (1), p.246
• Main Authors: Chai, Amanda B, Hartz, Anika M S, Gao, Xuexin, Yang, Alryel, Callaghan, Richard, Gelissen, Ingrid C
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - etiology; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; Binding sites; Blood-brain barrier; Blood-Brain Barrier - metabolism; Brain - metabolism; Capillaries; Capillaries - metabolism; Cell Line, Tumor; Cell Survival; CHO Cells; Cricetulus; Drug dosages; Endothelium; Exports; Gene Expression; Humans; Hydrophobicity; Isoforms; Ligands; Membranes; Neurogenesis; Neurons; Neurons - metabolism; Neurotoxicity; P-Glycoprotein; Pathology; Peptide Fragments - metabolism; Peptides; Protein Binding; Protein Transport; Proteins; Verapamil
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22010246

Defective clearance mechanisms lead to the accumulation of amyloid-beta (Aβ) peptides in the Alzheimer's brain. Though predominantly generated in neurons, little is known about how these hydrophobic, aggregation-prone, and tightly membrane-associated peptides exit into the extracellular space where they deposit and propagate neurotoxicity. The ability for P-glycoprotein (P-gp), an ATP-binding cassette (ABC) transporter, to export Aβ across the blood-brain barrier (BBB) has previously been reported. However, controversies surrounding the P-gp-Aβ interaction persist. Here, molecular data affirm that both Aβ and Aβ peptide isoforms directly interact with and are substrates of P-gp. This was reinforced ex vivo by the inhibition of Aβ transport in brain capillaries from P-gp-knockout mice. Moreover, we explored whether P-gp could exert the same role in neurons. Comparison between non-neuronal CHO-APP and human neuroblastoma SK-N-SH cells revealed that P-gp is expressed and active in both cell types. Inhibiting P-gp activity using verapamil and nicardipine impaired Aβ and Aβ secretion from both cell types, as determined by ELISA. Collectively, these findings implicate P-gp in Aβ export from neurons, as well as across the BBB endothelium, and suggest that restoring or enhancing P-gp function could be a viable therapeutic approach for removing excess Aβ out of the brain in Alzheimer's disease.