Mechanism of thioflavin T accumulation inside cells overexpressing P-glycoprotein or multidrug resistance-associated protein: role of lipophilicity and positive charge.
Alzheimer's disease is characterized by the presence of amyloid deposition. Thioflavin T (ThT) has been one of the molecules of choice to attempt the detection of these amyloid deposits. However, it has been reported that ThT was unable to cross blood-brain barrier (BBB). Our aim was to understand the mechanism according to which it has been said that ThT is not able to cross the BBB. For this purpose we have used cellular models overexpressing P-glycoprotein (P-gp) or multidrug resistance-associated protein (MRP1), two proteins overexpressed in BBB. Our results show that: (i) ThT is able to cross membranes and to penetrate inside the cells; (ii) ThT is a P-gp substrate; (iii) ThT is poor MRP1 substrate. In conclusion, our results suggest that two factors could be involved in the low accumulation of ThT in the brain: ThT is a P-gp substrate and its lipophilicity is low.
Darghal
Nacira
N
Laboratoire de Biophysique Moléculaire, Cellulaire et Tissulaire (BioMoCeTi), UMR CNRS 7033, Université Paris 13 et Paris 6, 74 rue Marcel Cachin, 93017 Bobigny, France.
Garnier-Suillerot
Arlette
A
Salerno
Milena
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D052160:Benzothiazoles; D001812:Blood-Brain Barrier / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute / Q000378:metabolism; D050356:Lipid Metabolism; D008657:Metabolic Clearance Rate; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D055672:Static Electricity; D013844:Thiazoles / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D052160:Benzothiazoles; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D013844:Thiazoles; C009462:thioflavin T; C421109:multidrug resistance-associated protein 1