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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

Electron micrographs of Aβ1-42 (20 μM) assembled alone or with 1 μM bis(heptyl)-cognitin or with 10 μM tacrine at various time points as indicated.The high power images are enlarged from low power images. Scale bar = 100 nm.
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f6: Electron micrographs of Aβ1-42 (20 μM) assembled alone or with 1 μM bis(heptyl)-cognitin or with 10 μM tacrine at various time points as indicated.The high power images are enlarged from low power images. Scale bar = 100 nm.

Mentions: To determine the morphology of Aβ1-42 assemblies in the samples, TEM was used. Globular Aβ1-42 oligomers with diameters of about 10-20 nm were detected predominantly in the untreated Aβ1-42 samples (Fig. 6). In contrast, mostly large chain-like assemblies were observed in the bis(heptyl)-cognitin-treated samples (Fig. 6). These chain-like assemblies were detected even at 15 min after bis(heptyl)-cognitin and Aβ1-42 co-incubation. Globular oligomers were mainly observed in the tacrine-treated samples (Fig. 6).


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)

Electron micrographs of Aβ1-42 (20 μM) assembled alone or with 1 μM bis(heptyl)-cognitin or with 10 μM tacrine at various time points as indicated.The high power images are enlarged from low power images. Scale bar = 100 nm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f6: Electron micrographs of Aβ1-42 (20 μM) assembled alone or with 1 μM bis(heptyl)-cognitin or with 10 μM tacrine at various time points as indicated.The high power images are enlarged from low power images. Scale bar = 100 nm.
Mentions: To determine the morphology of Aβ1-42 assemblies in the samples, TEM was used. Globular Aβ1-42 oligomers with diameters of about 10-20 nm were detected predominantly in the untreated Aβ1-42 samples (Fig. 6). In contrast, mostly large chain-like assemblies were observed in the bis(heptyl)-cognitin-treated samples (Fig. 6). These chain-like assemblies were detected even at 15 min after bis(heptyl)-cognitin and Aβ1-42 co-incubation. Globular oligomers were mainly observed in the tacrine-treated samples (Fig. 6).

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