title: The Effects of Latrepirdine on Amyloid-β Aggregation and Toxicity.
abstract: Latrepirdine (Dimebon) 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-β (Aβ) 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 Aβ:latrepirdine and with lower concentrations of latrepirdine. The ability of latrepirdine to alter the formation of Aβ42 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 Aβ 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 Aβ 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 Aβ 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.
authors.affiliation: School of Biomedical Sciences, CHIRI Biosciences Research Precinct, Faculty of Health Sciences, Curtin University, Western Australia, Australia.|Centre of Excellence for Alzheimer's Disease Research and Care, School of Medical Sciences, Edith Cowan University, Western Australia, Australia.
authors.forename: Tenielle
authors.initials: T
authors.lastname: Porter
authors.affiliation: School of Biomedical Sciences, CHIRI Biosciences Research Precinct, Faculty of Health Sciences, Curtin University, Western Australia, Australia.|Centre of Excellence for Alzheimer's Disease Research and Care, School of Medical Sciences, Edith Cowan University, Western Australia, Australia.
authors.forename: Prashant
authors.initials: P
authors.lastname: Bharadwaj
authors.affiliation: School of Biomedical Sciences, CHIRI Biosciences Research Precinct, Faculty of Health Sciences, Curtin University, Western Australia, Australia.|School of Psychiatry and Clinical Neuroscience, University of Western Australia, Western Australia, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Groth
authors.affiliation: School of Biomedical Sciences, CHIRI Biosciences Research Precinct, Faculty of Health Sciences, Curtin University, Western Australia, Australia.
authors.forename: Adrian
authors.initials: A
authors.lastname: Paxman
authors.affiliation: Centre of Excellence for Alzheimer's Disease Research and Care, School of Medical Sciences, Edith Cowan University, Western Australia, Australia.
authors.forename: Simon M
authors.initials: SM
authors.lastname: Laws
authors.affiliation: Centre of Excellence for Alzheimer's Disease Research and Care, School of Medical Sciences, Edith Cowan University, Western Australia, Australia.|School of Psychiatry and Clinical Neuroscience, University of Western Australia, Western Australia, Australia.|The Sir James McCusker Alzheimer's Disease Research Unit, Hollywood Private Hospital, Western Australia, Australia.
authors.forename: Ralph N
authors.initials: RN
authors.lastname: Martins
authors.affiliation: School of Biomedical Sciences, CHIRI Biosciences Research Precinct, Faculty of Health Sciences, Curtin University, Western Australia, Australia.|Centre of Excellence for Alzheimer's Disease Research and Care, School of Medical Sciences, Edith Cowan University, Western Australia, Australia.|School of Psychiatry and Clinical Neuroscience, University of Western Australia, Western Australia, Australia.|The Sir James McCusker Alzheimer's Disease Research Unit, Hollywood Private Hospital, Western Australia, Australia.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Verdile
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity*; D000704:Analysis of Variance; D014150:Antipsychotic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D018625:Microscopy, Atomic Force; D009447:Neuroblastoma / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism* / Q000633:toxicity*; D066329:Protein Aggregates / Q000187:drug effects*
chemical_list: D016229:Amyloid beta-Peptides; D014150:Antipsychotic Agents; D007211:Indoles; D010446:Peptide Fragments; D066329:Protein Aggregates; C075222:amyloid beta-protein (1-42); D007770:L-Lactate Dehydrogenase; C010119:latrepirdine
keywords: Alzheimer’s disease; Thiofavin T; amyloid-beta; latrepirdine; neurotoxicity
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