Limits...
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 changes transitions in secondary structure during Aβ assembly.Changes in secondary structure indicated by far-UV CD during assembly of 20 μM Aβ1-42 alone or with 1 μM bis(heptyl)-cognitin or 10 μM tacrine. Aliquots of reactions (200 μl) were transferred at various times to a CD cuvette, and spectra were recorded. Representative spectra are shown for Aβ1-42 samples taken at the indicated times alone (A) in the presence of 1 μM bis(heptyl)-cognitin (B) or 10 μM tacrine (C). The spectra presented at each time were representative of those obtained during each of the five independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4508546&req=5

f5: Bis(heptyl)-cognitin changes transitions in secondary structure during Aβ assembly.Changes in secondary structure indicated by far-UV CD during assembly of 20 μM Aβ1-42 alone or with 1 μM bis(heptyl)-cognitin or 10 μM tacrine. Aliquots of reactions (200 μl) were transferred at various times to a CD cuvette, and spectra were recorded. Representative spectra are shown for Aβ1-42 samples taken at the indicated times alone (A) in the presence of 1 μM bis(heptyl)-cognitin (B) or 10 μM tacrine (C). The spectra presented at each time were representative of those obtained during each of the five independent experiments.

Mentions: To further examine whether bis(heptyl)-cognitin modified the secondary structure of Aβ during Aβ assembly, we undertook CD studies. Aβ1-42, incubated alone, produced the initial spectra characteristic (Fig. 5A). Aβ1-42 displayed substantial secondary structural changes between 15 min and 2d, results that were consistent with previously reported pro-β-sheet transitions associated with monomer-protofibril-fibril assembly. When 20 μM Aβ1-42 was incubated with 1 μM bis(heptyl)-cognitin, no such transitions were observed (Fig. 5B), suggesting that bis(heptyl)-cognitin modified the secondary structural changes during Aβ assembly. Tacrine hardly changed the initial spectral characteristic of Aβ during Aβ assembly (Fig. 5C).


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 changes transitions in secondary structure during Aβ assembly.Changes in secondary structure indicated by far-UV CD during assembly of 20 μM Aβ1-42 alone or with 1 μM bis(heptyl)-cognitin or 10 μM tacrine. Aliquots of reactions (200 μl) were transferred at various times to a CD cuvette, and spectra were recorded. Representative spectra are shown for Aβ1-42 samples taken at the indicated times alone (A) in the presence of 1 μM bis(heptyl)-cognitin (B) or 10 μM tacrine (C). The spectra presented at each time were representative of those obtained during each of the five independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5: Bis(heptyl)-cognitin changes transitions in secondary structure during Aβ assembly.Changes in secondary structure indicated by far-UV CD during assembly of 20 μM Aβ1-42 alone or with 1 μM bis(heptyl)-cognitin or 10 μM tacrine. Aliquots of reactions (200 μl) were transferred at various times to a CD cuvette, and spectra were recorded. Representative spectra are shown for Aβ1-42 samples taken at the indicated times alone (A) in the presence of 1 μM bis(heptyl)-cognitin (B) or 10 μM tacrine (C). The spectra presented at each time were representative of those obtained during each of the five independent experiments.
Mentions: To further examine whether bis(heptyl)-cognitin modified the secondary structure of Aβ during Aβ assembly, we undertook CD studies. Aβ1-42, incubated alone, produced the initial spectra characteristic (Fig. 5A). Aβ1-42 displayed substantial secondary structural changes between 15 min and 2d, results that were consistent with previously reported pro-β-sheet transitions associated with monomer-protofibril-fibril assembly. When 20 μM Aβ1-42 was incubated with 1 μM bis(heptyl)-cognitin, no such transitions were observed (Fig. 5B), suggesting that bis(heptyl)-cognitin modified the secondary structural changes during Aβ assembly. Tacrine hardly changed the initial spectral characteristic of Aβ during Aβ assembly (Fig. 5C).

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