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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 tacrine, prevents Aβ1-42 oligomers-induced synaptotoxicity in primary mature hippocampal neurons.(A) Aβ1-42 oligomers reduce neurite length in hippocampal neurons. After DIV14, hippocampal neurons were treated for 4 d with various concentrations of Aβ1-42 oligomers prior to fixation and analysis for the length of βIII-tubulin positive neurites by using NeuriteTracer program. (B) Hippocampal neurons were pre-incubated with 0.3 μM bis(heptyl)-cognitin, 10 μM tacrine or 10 μM curcumin, and exposed to 1 μM Aβ1-42 oligomers 2 h later. Four days after Aβ1-42 oligomers challenge, neurons were fixed. Upper: Neuronal cultures were stained with anti-βIII-tubulin antibody. Lower: βIII-tubulin positive neurites were digitally identified and skeletonized for quantification by NeuriteTracer program (scale bar: 10 μM). (C) Hippocampal neurons were pre-incubated with various treatments as indicated and exposed to 1 μM Aβ1-42 oligomers 2 h later. Four days after Aβ1-42 oligomers challenge, neurons were fixed and analyzed for the length of βIII-tubulin positive neurites by using NeuriteTracer program. (D) Hippocampal neurons were pre-incubated with 0.3 μM bis(heptyl)-cognitin, 10 μM tacrine or 10 μM curcumin and exposed to 1 μM Aβ1-42 oligomers 2 h later. Four days after Aβ1-42 oligomers challenge, neurons were fixed and labeled with βIII-tubulin and synapsin I antibodies (scale bar: 10 μM). (E) Synapsin I integrated immunofluorescence intensity was evaluated by using ImageJ. r.u.: relative unit. Data represent means ± SEM (5 images were analyzed in each group), **p < 0.01 vs. control in (A); *p < 0.05 and **p < 0.01 vs. Aβ1-42 oligomers group in (C) and (E) (ANOVA and Dunnett’s test).
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f3: Bis(heptyl)-cognitin, but not tacrine, prevents Aβ1-42 oligomers-induced synaptotoxicity in primary mature hippocampal neurons.(A) Aβ1-42 oligomers reduce neurite length in hippocampal neurons. After DIV14, hippocampal neurons were treated for 4 d with various concentrations of Aβ1-42 oligomers prior to fixation and analysis for the length of βIII-tubulin positive neurites by using NeuriteTracer program. (B) Hippocampal neurons were pre-incubated with 0.3 μM bis(heptyl)-cognitin, 10 μM tacrine or 10 μM curcumin, and exposed to 1 μM Aβ1-42 oligomers 2 h later. Four days after Aβ1-42 oligomers challenge, neurons were fixed. Upper: Neuronal cultures were stained with anti-βIII-tubulin antibody. Lower: βIII-tubulin positive neurites were digitally identified and skeletonized for quantification by NeuriteTracer program (scale bar: 10 μM). (C) Hippocampal neurons were pre-incubated with various treatments as indicated and exposed to 1 μM Aβ1-42 oligomers 2 h later. Four days after Aβ1-42 oligomers challenge, neurons were fixed and analyzed for the length of βIII-tubulin positive neurites by using NeuriteTracer program. (D) Hippocampal neurons were pre-incubated with 0.3 μM bis(heptyl)-cognitin, 10 μM tacrine or 10 μM curcumin and exposed to 1 μM Aβ1-42 oligomers 2 h later. Four days after Aβ1-42 oligomers challenge, neurons were fixed and labeled with βIII-tubulin and synapsin I antibodies (scale bar: 10 μM). (E) Synapsin I integrated immunofluorescence intensity was evaluated by using ImageJ. r.u.: relative unit. Data represent means ± SEM (5 images were analyzed in each group), **p < 0.01 vs. control in (A); *p < 0.05 and **p < 0.01 vs. Aβ1-42 oligomers group in (C) and (E) (ANOVA and Dunnett’s test).

Mentions: It is well established that Aβ1-42 oligomers not only inhibit synaptic plasticity, but also induce synaptotoxicity in hippocampal neurons13. To further study the effects of bis(heptyl)-cognitin on the prevention of synaptic impairments, an immunostaining-based quantitative study was used. At 14 day in vitro (DIV), primary mature hippocampal neurons were exposed to Aβ1-42 oligomers for 4d. Aβ1-42 oligomers (0.1-1.5 μM) caused a concentration-dependent reduction in the length of βIII-tubulin positive neurites with a threshold concentration of 1 μM (Fig. 3A).


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 tacrine, prevents Aβ1-42 oligomers-induced synaptotoxicity in primary mature hippocampal neurons.(A) Aβ1-42 oligomers reduce neurite length in hippocampal neurons. After DIV14, hippocampal neurons were treated for 4 d with various concentrations of Aβ1-42 oligomers prior to fixation and analysis for the length of βIII-tubulin positive neurites by using NeuriteTracer program. (B) Hippocampal neurons were pre-incubated with 0.3 μM bis(heptyl)-cognitin, 10 μM tacrine or 10 μM curcumin, and exposed to 1 μM Aβ1-42 oligomers 2 h later. Four days after Aβ1-42 oligomers challenge, neurons were fixed. Upper: Neuronal cultures were stained with anti-βIII-tubulin antibody. Lower: βIII-tubulin positive neurites were digitally identified and skeletonized for quantification by NeuriteTracer program (scale bar: 10 μM). (C) Hippocampal neurons were pre-incubated with various treatments as indicated and exposed to 1 μM Aβ1-42 oligomers 2 h later. Four days after Aβ1-42 oligomers challenge, neurons were fixed and analyzed for the length of βIII-tubulin positive neurites by using NeuriteTracer program. (D) Hippocampal neurons were pre-incubated with 0.3 μM bis(heptyl)-cognitin, 10 μM tacrine or 10 μM curcumin and exposed to 1 μM Aβ1-42 oligomers 2 h later. Four days after Aβ1-42 oligomers challenge, neurons were fixed and labeled with βIII-tubulin and synapsin I antibodies (scale bar: 10 μM). (E) Synapsin I integrated immunofluorescence intensity was evaluated by using ImageJ. r.u.: relative unit. Data represent means ± SEM (5 images were analyzed in each group), **p < 0.01 vs. control in (A); *p < 0.05 and **p < 0.01 vs. Aβ1-42 oligomers group in (C) and (E) (ANOVA and Dunnett’s test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4508546&req=5

f3: Bis(heptyl)-cognitin, but not tacrine, prevents Aβ1-42 oligomers-induced synaptotoxicity in primary mature hippocampal neurons.(A) Aβ1-42 oligomers reduce neurite length in hippocampal neurons. After DIV14, hippocampal neurons were treated for 4 d with various concentrations of Aβ1-42 oligomers prior to fixation and analysis for the length of βIII-tubulin positive neurites by using NeuriteTracer program. (B) Hippocampal neurons were pre-incubated with 0.3 μM bis(heptyl)-cognitin, 10 μM tacrine or 10 μM curcumin, and exposed to 1 μM Aβ1-42 oligomers 2 h later. Four days after Aβ1-42 oligomers challenge, neurons were fixed. Upper: Neuronal cultures were stained with anti-βIII-tubulin antibody. Lower: βIII-tubulin positive neurites were digitally identified and skeletonized for quantification by NeuriteTracer program (scale bar: 10 μM). (C) Hippocampal neurons were pre-incubated with various treatments as indicated and exposed to 1 μM Aβ1-42 oligomers 2 h later. Four days after Aβ1-42 oligomers challenge, neurons were fixed and analyzed for the length of βIII-tubulin positive neurites by using NeuriteTracer program. (D) Hippocampal neurons were pre-incubated with 0.3 μM bis(heptyl)-cognitin, 10 μM tacrine or 10 μM curcumin and exposed to 1 μM Aβ1-42 oligomers 2 h later. Four days after Aβ1-42 oligomers challenge, neurons were fixed and labeled with βIII-tubulin and synapsin I antibodies (scale bar: 10 μM). (E) Synapsin I integrated immunofluorescence intensity was evaluated by using ImageJ. r.u.: relative unit. Data represent means ± SEM (5 images were analyzed in each group), **p < 0.01 vs. control in (A); *p < 0.05 and **p < 0.01 vs. Aβ1-42 oligomers group in (C) and (E) (ANOVA and Dunnett’s test).
Mentions: It is well established that Aβ1-42 oligomers not only inhibit synaptic plasticity, but also induce synaptotoxicity in hippocampal neurons13. To further study the effects of bis(heptyl)-cognitin on the prevention of synaptic impairments, an immunostaining-based quantitative study was used. At 14 day in vitro (DIV), primary mature hippocampal neurons were exposed to Aβ1-42 oligomers for 4d. Aβ1-42 oligomers (0.1-1.5 μM) caused a concentration-dependent reduction in the length of βIII-tubulin positive neurites with a threshold concentration of 1 μM (Fig. 3A).

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