Inflammation-induced dysfunction of the low-density lipoprotein receptor-related protein-1 at the blood-brain barrier: protection by the antioxidant N-acetylcysteine.
Impairment in two blood-brain barrier (BBB) efflux transporters, p-glycoprotein (Pgp) and low-density lipoprotein receptor-related protein-1 (LRP-1) are thought to contribute to the progression of Alzheimer's disease (AD) by resulting in the brain accumulation of their substrate amyloid beta peptide (Aβ). The initial cause of impaired efflux, however, is unknown. We have shown that induction of systemic inflammation by intraperitoneal administration of lipopolysaccharide impairs the efflux of Aβ from the brain, suggesting that systemic inflammation could be one such initiator. In this study, we determined whether pre-administration of the antioxidant N-aceytlcysteine (Nac) has a protective effect against LPS-induced Aβ transporter dysfunction. Our findings were that Nac protected against LPS-induced Aβ transport dysfunction at the BBB through an LRP-1-dependent and Pgp-independent mechanism. This was associated with Nac exerting antioxidant effects in the periphery but not the brain, despite an increased rate of entry of Nac into the brain following LPS. We also found that Nac pre-administration resulted in lower blood levels of the cytokines and chemokines interferon-γ, interleukin-10, CCL2, CCL4, and CCL5, but only lowered CCL4 in the cerebral cortex and hippocampus. Finally, we observed that hippocampal cytokine responses to LPS were decreased compared to cortex. These findings demonstrate a novel mechanism by which antioxidants prevent Aβ accumulation in the brain caused by inflammation, and therefore protect against AD.
Saint Louis University, Department of Pharmacology and Physiology, St Louis, MO, USA. mericks9@slu.edu
Michelle A
MA
Erickson
Kim
K
Hansen
William A
WA
Banks
D000111:Acetylcysteine / Q000378:metabolism / Q000494:pharmacology*; D000465:Algorithms; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D018925:Chemokines / Q000097:blood / Q000378:metabolism; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D008070:Lipopolysaccharides; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D050050:Protein Carbonylation / Q000187:drug effects; D011973:Receptors, LDL / Q000378:metabolism*; D012709:Serum Albumin / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D014700:Verapamil / Q000378:metabolism; D000511:alpha-Macroglobulins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002121:Calcium Channel Blockers; D018925:Chemokines; D016207:Cytokines; D008070:Lipopolysaccharides; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D011973:Receptors, LDL; D012709:Serum Albumin; D025521:Tumor Suppressor Proteins; D000511:alpha-Macroglobulins; D014700:Verapamil; D005978:Glutathione; D000111:Acetylcysteine