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Protection against β-amyloid-induced synaptic and memory impairments via altering β-amyloid assembly by bis(heptyl)-cognitin.

Chang L, Cui W, Yang Y, Xu S, Zhou W, Fu H, Hu S, Mak S, Hu J, Wang Q, Ma VP, Choi TC, Ma ED, Tao L, Pang Y, Rowan MJ, Anwyl R, Han Y, Wang Q - Sci Rep (2015)

Bottom Line: Molecular docking analysis further suggested that bis(heptyl)-cognitin presumably interacted with the hydrophobic pockets of Aβ, which confers stabilizing powers and assembly alteration effects on Aβ.Most importantly, bis(heptyl)-cognitin significantly reduced cognitive impairments induced by intra-hippocampal infusion of Aβ oligomers in mice.These results clearly demonstrated how dimeric agents prevent Aβ oligomers-induced synaptic and memory impairments, and offered a strong support for the beneficial therapeutic effects of bis(heptyl)-cognitin in the treatment of AD.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University. Ningbo 315211, China.

ABSTRACT
β-amyloid (Aβ) oligomers have been closely implicated in the pathogenesis of Alzheimer's disease (AD). We found, for the first time, that bis(heptyl)-cognitin, a novel dimeric acetylcholinesterase (AChE) inhibitor derived from tacrine, prevented Aβ oligomers-induced inhibition of long-term potentiation (LTP) at concentrations that did not interfere with normal LTP. Bis(heptyl)-cognitin also prevented Aβ oligomers-induced synaptotoxicity in primary hippocampal neurons. In contrast, tacrine and donepezil, typical AChE inhibitors, could not prevent synaptic impairments in these models, indicating that the modification of Aβ oligomers toxicity by bis(heptyl)-cognitin might be attributed to a mechanism other than AChE inhibition. Studies by using dot blotting, immunoblotting, circular dichroism spectroscopy, and transmission electron microscopy have shown that bis(heptyl)-cognitin altered Aβ assembly via directly inhibiting Aβ oligomers formation and reducing the amount of preformed Aβ oligomers. Molecular docking analysis further suggested that bis(heptyl)-cognitin presumably interacted with the hydrophobic pockets of Aβ, which confers stabilizing powers and assembly alteration effects on Aβ. Most importantly, bis(heptyl)-cognitin significantly reduced cognitive impairments induced by intra-hippocampal infusion of Aβ oligomers in mice. These results clearly demonstrated how dimeric agents prevent Aβ oligomers-induced synaptic and memory impairments, and offered a strong support for the beneficial therapeutic effects of bis(heptyl)-cognitin in the treatment of AD.

No MeSH data available.


Related in: MedlinePlus

Bis(heptyl)-cognitin, but not other AChE inhibitors, enhances HFS-induced LTP, and prevents Aβ oligomers-induced inhibition of LTP at low concentrations.(A) Aβ1-42 oligomers inhibit HFS-induced LTP. The graph shows the induction of LTP by vehicle (filled circles) or by 0.5 μM Aβ1-42 oligomers, perfused for 45 min prior to HFS (filled triangle). (B-D) Bis(heptyl)-cognitin (3 μM), tacrine (20 μM) and donepezil (10 μM) enhance HFS-induced LTP, and prevent Aβ1-42 oligomers-induced inhibition of LTP. Bis(heptyl)-cognitin, tacrine and donepezil were perfused over the slices for 60 min prior to HFS. (E) Bis(heptyl)-cognitin (3 μM), tacrine (20 μM) and donepezil (10 μM) enhance HFS-induced LTP. (F) Bis(heptyl)-cognitin (3 μM), tacrine (20 μM) and donepezil (10 μM) prevent Aβ1-42 oligomers-induced inhibition of LTP. Bis(heptyl)-cognitin, tacrine and donepezil were perfused over the slices for 60 min prior to HFS. After 15 min, Aβ1-42 oligomers were perfused. (G-I) The concentration-dependent effects of bis(heptyl)-cognitin (G), tacrine (H) or donepezil (I) on Aβ1-42 oligomers-induced inhibition of LTP. Data represent means ± SEM (n = 5). *p < 0.05 and **p < 0.01 vs. vehicle group in (E); and **p < 0.01 vs. Aβ1-42 oligomers group in (F-I) (ANOVA and Tukey’s test).
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f1: Bis(heptyl)-cognitin, but not other AChE inhibitors, enhances HFS-induced LTP, and prevents Aβ oligomers-induced inhibition of LTP at low concentrations.(A) Aβ1-42 oligomers inhibit HFS-induced LTP. The graph shows the induction of LTP by vehicle (filled circles) or by 0.5 μM Aβ1-42 oligomers, perfused for 45 min prior to HFS (filled triangle). (B-D) Bis(heptyl)-cognitin (3 μM), tacrine (20 μM) and donepezil (10 μM) enhance HFS-induced LTP, and prevent Aβ1-42 oligomers-induced inhibition of LTP. Bis(heptyl)-cognitin, tacrine and donepezil were perfused over the slices for 60 min prior to HFS. (E) Bis(heptyl)-cognitin (3 μM), tacrine (20 μM) and donepezil (10 μM) enhance HFS-induced LTP. (F) Bis(heptyl)-cognitin (3 μM), tacrine (20 μM) and donepezil (10 μM) prevent Aβ1-42 oligomers-induced inhibition of LTP. Bis(heptyl)-cognitin, tacrine and donepezil were perfused over the slices for 60 min prior to HFS. After 15 min, Aβ1-42 oligomers were perfused. (G-I) The concentration-dependent effects of bis(heptyl)-cognitin (G), tacrine (H) or donepezil (I) on Aβ1-42 oligomers-induced inhibition of LTP. Data represent means ± SEM (n = 5). *p < 0.05 and **p < 0.01 vs. vehicle group in (E); and **p < 0.01 vs. Aβ1-42 oligomers group in (F-I) (ANOVA and Tukey’s test).

Mentions: Consistent with our previous studies2223, HFS induced NMDA receptor-dependent LTP. The average LTP measurement was 149 ± 10% at 60 min post-HFS (n = 6; Fig. 1A,E). In order to study the effects of bis(heptyl)-cognitin on LTP, we first chose a concentration of bis(heptyl)-cognitin that had been reported to be effective against neuronal apoptosis (1 μM)24. Two typical AChE inhibitors, tacrine and donepezil, were used in concentrations that were chosen by their AChE inhibition and therapeutic ranges725. AChE inhibitors were applied 60 min before application of HFS and they remained present throughout the experiments. Although other AChE inhibitors at high concentrations significantly enhanced LTP following HFS compared to vehicle control (20 μM tacrine, n = 5, p < 0.01 compared to vehicle LTP; 10 μM donepezil, n = 5, p < 0.01 compared to vehicle LTP; Fig. 1E), they failed to increase HFS-induced LTP at low concentrations (3 μM tacrine, n = 5, p > 0.05 compared to vehicle LTP; 3 μM donepezil, n = 5, p > 0.05 compared to vehicle LTP; Fig. 1E). In comparison to vehicle LTP, 3 μM bis(heptyl)-cognitin enhanced HFS-induced LTP (n = 5, p < 0.05, Fig. 1E).


Protection against β-amyloid-induced synaptic and memory impairments via altering β-amyloid assembly by bis(heptyl)-cognitin.

Chang L, Cui W, Yang Y, Xu S, Zhou W, Fu H, Hu S, Mak S, Hu J, Wang Q, Ma VP, Choi TC, Ma ED, Tao L, Pang Y, Rowan MJ, Anwyl R, Han Y, Wang Q - Sci Rep (2015)

Bis(heptyl)-cognitin, but not other AChE inhibitors, enhances HFS-induced LTP, and prevents Aβ oligomers-induced inhibition of LTP at low concentrations.(A) Aβ1-42 oligomers inhibit HFS-induced LTP. The graph shows the induction of LTP by vehicle (filled circles) or by 0.5 μM Aβ1-42 oligomers, perfused for 45 min prior to HFS (filled triangle). (B-D) Bis(heptyl)-cognitin (3 μM), tacrine (20 μM) and donepezil (10 μM) enhance HFS-induced LTP, and prevent Aβ1-42 oligomers-induced inhibition of LTP. Bis(heptyl)-cognitin, tacrine and donepezil were perfused over the slices for 60 min prior to HFS. (E) Bis(heptyl)-cognitin (3 μM), tacrine (20 μM) and donepezil (10 μM) enhance HFS-induced LTP. (F) Bis(heptyl)-cognitin (3 μM), tacrine (20 μM) and donepezil (10 μM) prevent Aβ1-42 oligomers-induced inhibition of LTP. Bis(heptyl)-cognitin, tacrine and donepezil were perfused over the slices for 60 min prior to HFS. After 15 min, Aβ1-42 oligomers were perfused. (G-I) The concentration-dependent effects of bis(heptyl)-cognitin (G), tacrine (H) or donepezil (I) on Aβ1-42 oligomers-induced inhibition of LTP. Data represent means ± SEM (n = 5). *p < 0.05 and **p < 0.01 vs. vehicle group in (E); and **p < 0.01 vs. Aβ1-42 oligomers group in (F-I) (ANOVA and Tukey’s test).
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f1: Bis(heptyl)-cognitin, but not other AChE inhibitors, enhances HFS-induced LTP, and prevents Aβ oligomers-induced inhibition of LTP at low concentrations.(A) Aβ1-42 oligomers inhibit HFS-induced LTP. The graph shows the induction of LTP by vehicle (filled circles) or by 0.5 μM Aβ1-42 oligomers, perfused for 45 min prior to HFS (filled triangle). (B-D) Bis(heptyl)-cognitin (3 μM), tacrine (20 μM) and donepezil (10 μM) enhance HFS-induced LTP, and prevent Aβ1-42 oligomers-induced inhibition of LTP. Bis(heptyl)-cognitin, tacrine and donepezil were perfused over the slices for 60 min prior to HFS. (E) Bis(heptyl)-cognitin (3 μM), tacrine (20 μM) and donepezil (10 μM) enhance HFS-induced LTP. (F) Bis(heptyl)-cognitin (3 μM), tacrine (20 μM) and donepezil (10 μM) prevent Aβ1-42 oligomers-induced inhibition of LTP. Bis(heptyl)-cognitin, tacrine and donepezil were perfused over the slices for 60 min prior to HFS. After 15 min, Aβ1-42 oligomers were perfused. (G-I) The concentration-dependent effects of bis(heptyl)-cognitin (G), tacrine (H) or donepezil (I) on Aβ1-42 oligomers-induced inhibition of LTP. Data represent means ± SEM (n = 5). *p < 0.05 and **p < 0.01 vs. vehicle group in (E); and **p < 0.01 vs. Aβ1-42 oligomers group in (F-I) (ANOVA and Tukey’s test).
Mentions: Consistent with our previous studies2223, HFS induced NMDA receptor-dependent LTP. The average LTP measurement was 149 ± 10% at 60 min post-HFS (n = 6; Fig. 1A,E). In order to study the effects of bis(heptyl)-cognitin on LTP, we first chose a concentration of bis(heptyl)-cognitin that had been reported to be effective against neuronal apoptosis (1 μM)24. Two typical AChE inhibitors, tacrine and donepezil, were used in concentrations that were chosen by their AChE inhibition and therapeutic ranges725. AChE inhibitors were applied 60 min before application of HFS and they remained present throughout the experiments. Although other AChE inhibitors at high concentrations significantly enhanced LTP following HFS compared to vehicle control (20 μM tacrine, n = 5, p < 0.01 compared to vehicle LTP; 10 μM donepezil, n = 5, p < 0.01 compared to vehicle LTP; Fig. 1E), they failed to increase HFS-induced LTP at low concentrations (3 μM tacrine, n = 5, p > 0.05 compared to vehicle LTP; 3 μM donepezil, n = 5, p > 0.05 compared to vehicle LTP; Fig. 1E). In comparison to vehicle LTP, 3 μM bis(heptyl)-cognitin enhanced HFS-induced LTP (n = 5, p < 0.05, Fig. 1E).

Bottom Line: Molecular docking analysis further suggested that bis(heptyl)-cognitin presumably interacted with the hydrophobic pockets of Aβ, which confers stabilizing powers and assembly alteration effects on Aβ.Most importantly, bis(heptyl)-cognitin significantly reduced cognitive impairments induced by intra-hippocampal infusion of Aβ oligomers in mice.These results clearly demonstrated how dimeric agents prevent Aβ oligomers-induced synaptic and memory impairments, and offered a strong support for the beneficial therapeutic effects of bis(heptyl)-cognitin in the treatment of AD.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University. Ningbo 315211, China.

ABSTRACT
β-amyloid (Aβ) oligomers have been closely implicated in the pathogenesis of Alzheimer's disease (AD). We found, for the first time, that bis(heptyl)-cognitin, a novel dimeric acetylcholinesterase (AChE) inhibitor derived from tacrine, prevented Aβ oligomers-induced inhibition of long-term potentiation (LTP) at concentrations that did not interfere with normal LTP. Bis(heptyl)-cognitin also prevented Aβ oligomers-induced synaptotoxicity in primary hippocampal neurons. In contrast, tacrine and donepezil, typical AChE inhibitors, could not prevent synaptic impairments in these models, indicating that the modification of Aβ oligomers toxicity by bis(heptyl)-cognitin might be attributed to a mechanism other than AChE inhibition. Studies by using dot blotting, immunoblotting, circular dichroism spectroscopy, and transmission electron microscopy have shown that bis(heptyl)-cognitin altered Aβ assembly via directly inhibiting Aβ oligomers formation and reducing the amount of preformed Aβ oligomers. Molecular docking analysis further suggested that bis(heptyl)-cognitin presumably interacted with the hydrophobic pockets of Aβ, which confers stabilizing powers and assembly alteration effects on Aβ. Most importantly, bis(heptyl)-cognitin significantly reduced cognitive impairments induced by intra-hippocampal infusion of Aβ oligomers in mice. These results clearly demonstrated how dimeric agents prevent Aβ oligomers-induced synaptic and memory impairments, and offered a strong support for the beneficial therapeutic effects of bis(heptyl)-cognitin in the treatment of AD.

No MeSH data available.


Related in: MedlinePlus