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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

Blockage of α7nAChR could not abolish the prevention of Aβ1-42 oligomers-induced inhibition of LTP by bis(heptyl)-cognitin.(A-D) MLA and KT5720 block the enhancement of HFS-induced LTP, but not the prevention of Aβ1-42 oligomers-induced inhibition of LTP by bis(heptyl)-cognitin. Bis(heptyl)-cognitin, tacrine and kinase inhibitors were perfused over the slices for 60 min prior to HFS. After 15 min, Aβ1-42 oligomers were perfused. (E) α7nAChR mediates the enhancement of HFS-induced LTP caused by either bis(heptyl)-cognitin or tacrine. (F) Blockage of α7nAChR could not abolish the prevention of Aβ1-42 oligomers-induced inhibition of LTP by bis(heptyl)-cognitin. Data represent means ± SEM (n = 5). *p < 0.05 vs. vehicle; ##p < 0.01 or &&p < 0.01 vs. bis(heptyl)-cognitin or tacrine group, respectively in (E); **p < 0.01 vs. Aβ1-42 oligomers group; &&p < 0.01 vs. tacrine plus Aβ1-42 oligomers groups in (F) (ANOVA and Tukey’s test).
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f2: Blockage of α7nAChR could not abolish the prevention of Aβ1-42 oligomers-induced inhibition of LTP by bis(heptyl)-cognitin.(A-D) MLA and KT5720 block the enhancement of HFS-induced LTP, but not the prevention of Aβ1-42 oligomers-induced inhibition of LTP by bis(heptyl)-cognitin. Bis(heptyl)-cognitin, tacrine and kinase inhibitors were perfused over the slices for 60 min prior to HFS. After 15 min, Aβ1-42 oligomers were perfused. (E) α7nAChR mediates the enhancement of HFS-induced LTP caused by either bis(heptyl)-cognitin or tacrine. (F) Blockage of α7nAChR could not abolish the prevention of Aβ1-42 oligomers-induced inhibition of LTP by bis(heptyl)-cognitin. Data represent means ± SEM (n = 5). *p < 0.05 vs. vehicle; ##p < 0.01 or &&p < 0.01 vs. bis(heptyl)-cognitin or tacrine group, respectively in (E); **p < 0.01 vs. Aβ1-42 oligomers group; &&p < 0.01 vs. tacrine plus Aβ1-42 oligomers groups in (F) (ANOVA and Tukey’s test).

Mentions: AChE inhibitors could enhance HFS-induced LTP and prevent Aβ-mediated LTP inhibition via potentiating α7nAChR and activating downstream PKA pathway262728. In our study, MLA, a specific α7nAChR inhibitor, and KT5720, a specific inhibitor of PKA, could block the enhancement of HFS-induced LTP and the prevention of Aβ1-42 oligomers-induced inhibition of LTP by tacrine (Fig. 2E,F). Interestingly, although MLA and KT5720 reduced the increase of HFS-induced LTP caused by 3 μM bis(heptyl)-cognitin, neither of these agents affected the protection of bis(heptyl)-cognitin on Aβ1-42 oligomers-induced inhibition of LTP (Fig. 2E,F). Moreover, MG624 (a specific α7nAChR inhibitor) and H89 (a specific PKA inhibitor) could not abolish the protection of bis(heptyl)-cognitin on Aβ1-42 oligomers-induced inhibition of LTP (Fig. 2F). To date, none of these inhibitors altered baseline neurotransmission or the induction of LTP by HFS in our experiments.


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)

Blockage of α7nAChR could not abolish the prevention of Aβ1-42 oligomers-induced inhibition of LTP by bis(heptyl)-cognitin.(A-D) MLA and KT5720 block the enhancement of HFS-induced LTP, but not the prevention of Aβ1-42 oligomers-induced inhibition of LTP by bis(heptyl)-cognitin. Bis(heptyl)-cognitin, tacrine and kinase inhibitors were perfused over the slices for 60 min prior to HFS. After 15 min, Aβ1-42 oligomers were perfused. (E) α7nAChR mediates the enhancement of HFS-induced LTP caused by either bis(heptyl)-cognitin or tacrine. (F) Blockage of α7nAChR could not abolish the prevention of Aβ1-42 oligomers-induced inhibition of LTP by bis(heptyl)-cognitin. Data represent means ± SEM (n = 5). *p < 0.05 vs. vehicle; ##p < 0.01 or &&p < 0.01 vs. bis(heptyl)-cognitin or tacrine group, respectively in (E); **p < 0.01 vs. Aβ1-42 oligomers group; &&p < 0.01 vs. tacrine plus Aβ1-42 oligomers groups in (F) (ANOVA and Tukey’s test).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: Blockage of α7nAChR could not abolish the prevention of Aβ1-42 oligomers-induced inhibition of LTP by bis(heptyl)-cognitin.(A-D) MLA and KT5720 block the enhancement of HFS-induced LTP, but not the prevention of Aβ1-42 oligomers-induced inhibition of LTP by bis(heptyl)-cognitin. Bis(heptyl)-cognitin, tacrine and kinase inhibitors were perfused over the slices for 60 min prior to HFS. After 15 min, Aβ1-42 oligomers were perfused. (E) α7nAChR mediates the enhancement of HFS-induced LTP caused by either bis(heptyl)-cognitin or tacrine. (F) Blockage of α7nAChR could not abolish the prevention of Aβ1-42 oligomers-induced inhibition of LTP by bis(heptyl)-cognitin. Data represent means ± SEM (n = 5). *p < 0.05 vs. vehicle; ##p < 0.01 or &&p < 0.01 vs. bis(heptyl)-cognitin or tacrine group, respectively in (E); **p < 0.01 vs. Aβ1-42 oligomers group; &&p < 0.01 vs. tacrine plus Aβ1-42 oligomers groups in (F) (ANOVA and Tukey’s test).
Mentions: AChE inhibitors could enhance HFS-induced LTP and prevent Aβ-mediated LTP inhibition via potentiating α7nAChR and activating downstream PKA pathway262728. In our study, MLA, a specific α7nAChR inhibitor, and KT5720, a specific inhibitor of PKA, could block the enhancement of HFS-induced LTP and the prevention of Aβ1-42 oligomers-induced inhibition of LTP by tacrine (Fig. 2E,F). Interestingly, although MLA and KT5720 reduced the increase of HFS-induced LTP caused by 3 μM bis(heptyl)-cognitin, neither of these agents affected the protection of bis(heptyl)-cognitin on Aβ1-42 oligomers-induced inhibition of LTP (Fig. 2E,F). Moreover, MG624 (a specific α7nAChR inhibitor) and H89 (a specific PKA inhibitor) could not abolish the protection of bis(heptyl)-cognitin on Aβ1-42 oligomers-induced inhibition of LTP (Fig. 2F). To date, none of these inhibitors altered baseline neurotransmission or the induction of LTP by HFS in our experiments.

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