The Effects of Latrepirdine on Amyloid-ß Aggregation and Toxicity
MetadataShow full item record
© 2016 - IOS Press and the authors. All rights reserved. Latrepirdine (DimebonTM) has been demonstrated to be a neuroprotective and cognition improving agent in neurodegenerative diseases that feature protein aggregation and deposition, such as Alzheimer's disease (AD). The accumulation of amyloid-ß (Aß) protein aggregates is a key event in the neurodegenerative process in AD. This study explores if latrepirdine modulation of protein aggregation contributes to its neuroprotective mechanism of action. Assessment of neuronal cell death showed that there was a significant reduction in lactate dehydrogenase release at an equimolar ratio of Aß:latrepirdine and with lower concentrations of latrepirdine. The ability of latrepirdine to alter the formation of Aß42 aggregates was assessed by thioflavin-T fluorescence, western immunoblotting and atomic force microscopy (AFM). Despite showing a reduction in thioflavin-T fluorescence with latrepirdine treatment, indicating a decrease in aggregation, immunoblotting and AFM showed a modest increase in both the formation and size of Aß aggregates. The discrepancies between thioflavin-T and the other assays are consistent with previous evidence that cyclic molecules can interfere with thioflavin-T binding of amyloid protein preparations. The ability of latrepirdine to modulate Aß aggregation appears to be independent of its neuroprotective effects, and is unlikely to be a mechanism by which latrepirdine offers protection. This study investigates the effect of latrepirdine on Aß aggregation, and presents evidence suggesting that caution should be applied in the use of thioflavin-T fluorescence based assays as a method for screening compounds for protein aggregation altering properties.
open access https://creativecommons.org/licenses/by-nc/3.0/au/
Showing items related by title, author, creator and subject.
Bharadwaj, P.; Verdile, Giuseppe; Barr, R.; Gupta, V.; Steele, J.; Lachenmayer, M.; Yue, Z.; Ehrlich, M.; Petsko, G.; Ju, S.; Ringe, D.; Sankovich, S.; Caine, J.; Macreadie, I.; Gandy, S.; Martins, R. (2012)Latrepirdine (Dimebon™), an anti-histamine, has shown some benefits in trials of neurodegenerative diseases characterized by accumulation of aggregated or misfolded protein such as Alzheimer’s disease (AD) and has been ...
FTIR studies of the similarities between pathology induced protein aggregation in vivo and chemically induced protein aggregation ex vivoTidy, R.; Lam, V.; Fimognari, N.; Mamo, John; Hackett, M. (2016)© 2016 Elsevier B.V.Fourier transform infrared (FTIR) spectroscopy has been well documented to discriminate between protein secondary structures, at the micron scale. This capability has enabled in situ localization of ...
Novel bio-spectroscopic imaging reveals disturbed protein homeostasis and thiol redox with protein aggregation prior to hippocampal CA1 pyramidal neuron death induced by global brain ischemia in the ratHackett, Mark; Smith, S.; Caine, S.; Nichol, H.; George, G.; Pickering, I.; Paterson, P. (2015)Global brain ischemia resulting from cardiac arrest and cardiac surgery can lead to permanent brain damage and mental impairment. A clinical hallmark of global brain ischemia is delayed neurodegeneration, particularly ...