Cyclodextrins promote protein aggregation posing risks for therapeutic applications.
The presence of neurofibrillary tangles (NFTs) is a hallmark feature of various neurodegenerative disorders including Alzheimer's (AD) and Niemann-Pick type C (NPC) diseases. NFTs have been correlated with elevated cholesterol levels and a cholesterol-scavenging compound, cyclodextrin, effectively modulates and traffics cholesterol from cell bodies in NPC disease models. Cyclodextrins are also used as drug carriers to the blood-brain barrier (BBB) and other tissues. While cyclodextrins have potential value in treating brain diseases, it is important to determine how cyclodextrins affect natively unfolded proteins such as beta-amyloid (Abeta) whose aggregation has been correlated with AD. We show that cyclodextrins drastically alter Abeta aggregation kinetics and induce morphological changes to Abeta that can enhance toxicity towards SH-SY5Y human neuroblastoma cells. These results suggest that care must be taken when using cyclodextrins for BBB delivery or for treatment of brain disease because cyclodextrins can promote toxic aggregation of Abeta.
Wang
Min S
MS
Department of Chemical Engineering, Arizona State University, Tempe, AZ 85287-6006, USA.
Boddapati
Shanta
S
Sierks
Michael R
MR
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D001812:Blood-Brain Barrier / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003505:Cyclodextrins / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D016503:Drug Delivery Systems; D006801:Humans; D052556:Niemann-Pick Disease, Type C / Q000188:drug therapy / Q000378:metabolism
D016229:Amyloid beta-Peptides; D003505:Cyclodextrins