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    The Effects of Latrepirdine on Amyloid-ß Aggregation and Toxicity

    238370_238370.pdf (526.0Kb)
    Access Status
    Open access
    Authors
    Porter, T.
    Bharadwaj, P.
    Groth, David
    Paxman, A.
    Laws, S.
    Martins, R.
    Verdile, Giuseppe
    Date
    2016
    Type
    Journal Article
    
    Metadata
    Show full item record
    Citation
    Porter, T. and Bharadwaj, P. and Groth, D. and Paxman, A. and Laws, S. and Martins, R. and Verdile, G. 2016. The Effects of Latrepirdine on Amyloid-ß Aggregation and Toxicity. Journal of Alzheimer's Disease. 50 (3): pp. 895-905.
    Source Title
    Journal of Alzheimer's Disease
    DOI
    10.3233/JAD-150790
    ISSN
    1387-2877
    School
    School of Biomedical Sciences
    Remarks

    open access https://creativecommons.org/licenses/by-nc/3.0/au/

    URI
    http://hdl.handle.net/20.500.11937/41757
    Collection
    • Curtin Research Publications
    Abstract

    © 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.

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