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Dimeric bis (heptyl)-Cognitin Blocks Alzheimer's β-Amyloid Neurotoxicity Via the Inhibition of Aβ Fibrils Formation and Disaggregation of Preformed Fibrils
Hu S.-Q.1; Wang R.2; Cui W.1; Mak S.-H.1; Li G.4; Hu Y.-J.5; Lee M.-Y.5; Pang Y.-P.3; Han Y.-F.1
2015-12-01
Source PublicationCNS Neuroscience and Therapeutics
ISSN17555949 17555930
Volume21Issue:12Pages:953-961
AbstractAims: Fibrillar aggregates of β-amyloid protein (Aβ) are the main constituent of senile plaques and considered to be one of the causative events in the pathogenesis of Alzheimer's disease (AD). Compounds that could inhibit Aβ fibrils formation, disaggregate preformed Aβ fibrils as well as reduce their associated neurotoxicity might have therapeutic values for treating AD. In this study, the inhibitory effects of bis (heptyl)-cognitin (B7C), a multifunctional dimer derived from tacrine, on aggregation and neurotoxicity of Aβ were evaluated both in vitro and in vivo. Methods: Thioflavin T fluorescence assay was carried out to evaluate Aβ aggregation, MTT and Hoechst-staining assays were performed to investigate Aβ-associated neurotoxicity. Fluorescent probe DCFH-DA was used to estimate the accumulation of intracellular reactive oxygen stress (ROS). Morris water maze was applied to determine learning and memory deficits induced by intracerebroventricular infusion of Aβ in rats. Results: B7C (0.1-10 μM), but not tacrine, effectively inhibited Aβ fibrils formation and disaggregated preformed Aβ fibrils following co-incubation of B7C and Aβ monomers or preformed fibrils, respectively. In addition, B7C markedly reduced Aβ fibrils-associated neurotoxicity in SH-SY5Y cell line, as evidenced by the increase in cell survival, the decrease in Hoechst-stained nuclei and in intracellular ROS. Most encouragingly, B7C (0.1 and 0.2 mg/kg), 10 times more potently than tacrine (1 and 2 mg/kg), inhibited memory impairments after intracerebroventricular infusion of Aβ in rats, as evidenced by the decrease in escape latency and the increase in the spatial bias in Morris water maze test along with upregulation of choline acetyltransferase activity and downregulation of acetylcholinesterase activity. Conclusion: These findings provide not only novel molecular insight into the potential application of B7C in treating AD, but also an effective approach for screening anti-AD agents.
KeywordAlzheimer's disease Aβ fibrils Bis (heptyl)-cognitin Morris water maze Reactive oxygen stress Thioflavin T
DOI10.1111/cns.12472
URLView the original
Language英語
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被引频次[WOS]:8   [WOS记录]     [WOS相关记录]
Document TypeJournal article
专题University of Macau
Affiliation1.Hong Kong Polytechnic University
2.East China University of Science and Technology
3.Mayo Clinic
4.Soochow University
5.University of Macau
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Hu S.-Q.,Wang R.,Cui W.,et al. Dimeric bis (heptyl)-Cognitin Blocks Alzheimer's β-Amyloid Neurotoxicity Via the Inhibition of Aβ Fibrils Formation and Disaggregation of Preformed Fibrils[J]. CNS Neuroscience and Therapeutics,2015,21(12):953-961.
APA Hu S.-Q..,Wang R..,Cui W..,Mak S.-H..,Li G..,...&Han Y.-F..(2015).Dimeric bis (heptyl)-Cognitin Blocks Alzheimer's β-Amyloid Neurotoxicity Via the Inhibition of Aβ Fibrils Formation and Disaggregation of Preformed Fibrils.CNS Neuroscience and Therapeutics,21(12),953-961.
MLA Hu S.-Q.,et al."Dimeric bis (heptyl)-Cognitin Blocks Alzheimer's β-Amyloid Neurotoxicity Via the Inhibition of Aβ Fibrils Formation and Disaggregation of Preformed Fibrils".CNS Neuroscience and Therapeutics 21.12(2015):953-961.
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