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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

The potential interaction between bis(heptyl)-cognitin and Aβ.(A) Chemical structure of tacrine. (B) Chemical structure of bis(heptyl)-cognitin. Low-energy binding conformations of bis(heptyl)-cognitin (C) or tacrine (D) bound to the surface of Aβ assemblies (Gly33-Met35 and Met35-Gly37) generated by molecular docking. The small molecule is depicted as a ball-and-stick model showing carbon (yellow), nitrogen (blue), and hydrogen (dark grey) atoms. The Aβ assemblies are shown as skin representation.
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f7: The potential interaction between bis(heptyl)-cognitin and Aβ.(A) Chemical structure of tacrine. (B) Chemical structure of bis(heptyl)-cognitin. Low-energy binding conformations of bis(heptyl)-cognitin (C) or tacrine (D) bound to the surface of Aβ assemblies (Gly33-Met35 and Met35-Gly37) generated by molecular docking. The small molecule is depicted as a ball-and-stick model showing carbon (yellow), nitrogen (blue), and hydrogen (dark grey) atoms. The Aβ assemblies are shown as skin representation.

Mentions: To elucidate the mechanism underlying the alteration of Aβ assembly by bis(heptyl)-cognitin, we performed molecular docking analysis by using ICM-pro 3.6-1d molecular docking algorithm. Since no co-crystal structure of inhibitor with Aβ was available, the solution NMR structure of Aβ assemblies (PDB: 2BEG) was taken from PDB and used for docking analysis. In our model, no detectable hydrogen bonds between small molecules (bis(heptyl)-cognitin and tacrine) and Aβ assemblies were recorded. The interactions between small molecules and Aβ assemblies were mainly governed by hydrophobic interactions. Bis(heptyl)-cognitin was predicted to bind favorably to the hydrophobic clefts formed by Gly33-Met35 and Met35-Gly37 on the surface of Aβ1-42 (Fig. 7). Surprisingly, bis(heptyl)-cognitin situated longitudinally to Aβ assemblies where its two tacrine subunits tied up four to five units of Aβ1-42 molecules that are linked by the heptyl linkers, while the related monomer tacrine was only predicted to interact with two Aβ molecules (Fig. 7). Collectively, our results suggested that bis(heptyl)-cognitin presumably interacted with the hydrophobic pockets (Gly33-Met35 and Met35-Gly37) through multiple hydrophobic interactions which confers stabilizing powers and assembly alteration effects on Aβ.


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)

The potential interaction between bis(heptyl)-cognitin and Aβ.(A) Chemical structure of tacrine. (B) Chemical structure of bis(heptyl)-cognitin. Low-energy binding conformations of bis(heptyl)-cognitin (C) or tacrine (D) bound to the surface of Aβ assemblies (Gly33-Met35 and Met35-Gly37) generated by molecular docking. The small molecule is depicted as a ball-and-stick model showing carbon (yellow), nitrogen (blue), and hydrogen (dark grey) atoms. The Aβ assemblies are shown as skin representation.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f7: The potential interaction between bis(heptyl)-cognitin and Aβ.(A) Chemical structure of tacrine. (B) Chemical structure of bis(heptyl)-cognitin. Low-energy binding conformations of bis(heptyl)-cognitin (C) or tacrine (D) bound to the surface of Aβ assemblies (Gly33-Met35 and Met35-Gly37) generated by molecular docking. The small molecule is depicted as a ball-and-stick model showing carbon (yellow), nitrogen (blue), and hydrogen (dark grey) atoms. The Aβ assemblies are shown as skin representation.
Mentions: To elucidate the mechanism underlying the alteration of Aβ assembly by bis(heptyl)-cognitin, we performed molecular docking analysis by using ICM-pro 3.6-1d molecular docking algorithm. Since no co-crystal structure of inhibitor with Aβ was available, the solution NMR structure of Aβ assemblies (PDB: 2BEG) was taken from PDB and used for docking analysis. In our model, no detectable hydrogen bonds between small molecules (bis(heptyl)-cognitin and tacrine) and Aβ assemblies were recorded. The interactions between small molecules and Aβ assemblies were mainly governed by hydrophobic interactions. Bis(heptyl)-cognitin was predicted to bind favorably to the hydrophobic clefts formed by Gly33-Met35 and Met35-Gly37 on the surface of Aβ1-42 (Fig. 7). Surprisingly, bis(heptyl)-cognitin situated longitudinally to Aβ assemblies where its two tacrine subunits tied up four to five units of Aβ1-42 molecules that are linked by the heptyl linkers, while the related monomer tacrine was only predicted to interact with two Aβ molecules (Fig. 7). Collectively, our results suggested that bis(heptyl)-cognitin presumably interacted with the hydrophobic pockets (Gly33-Met35 and Met35-Gly37) through multiple hydrophobic interactions which confers stabilizing powers and assembly alteration effects on Aβ.

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