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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 prevents the memory deficits induced by intra-hippocampal infusion of Aβ1–42 oligomers in mice (n = 6 for each group).(A) The schedules of animal experiments. (B,C) Mean latencies to escape from the water onto the hidden platform. Each mouse was subjected to two trials per day for 4 consecutive days. (D) Upper: typical swimming-tracking path of vehicle control, Aβ1-42 oligomers-treated mice, bis(heptyl)-cognitin 0.2 mg/kg plus Aβ1-42 oligomers-treated mice, and tacrine 2 mg/kg plus Aβ1-42 oligomers-treated mice on the fourth training day. Lower: mean latencies to escape from the water onto the hidden platform on the fourth training day. (E) Upper: typical swimming-tracking path of of vehicle control, Aβ1-42 oligomers-treated mice, bis(heptyl)-cognitin 0.2 mg/kg plus Aβ1-42 oligomers-treated mice, and tacrine 2 mg/kg plus Aβ1-42 oligomers-treated mice in the probe trial. Lower: the swimming distance in the target quadrant (in which the platform had been placed during the training phase) in the probe trial. (F) Average swimming speed in the probe trial. Data represent means ± SEM. ###p < 0.001 vs. vehicle group; *p < 0.05 and **p < 0.01 vs. Aβ1-42 oligomers-treated group in (B-E) (Tukey’s test).
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f8: Bis(heptyl)-cognitin prevents the memory deficits induced by intra-hippocampal infusion of Aβ1–42 oligomers in mice (n = 6 for each group).(A) The schedules of animal experiments. (B,C) Mean latencies to escape from the water onto the hidden platform. Each mouse was subjected to two trials per day for 4 consecutive days. (D) Upper: typical swimming-tracking path of vehicle control, Aβ1-42 oligomers-treated mice, bis(heptyl)-cognitin 0.2 mg/kg plus Aβ1-42 oligomers-treated mice, and tacrine 2 mg/kg plus Aβ1-42 oligomers-treated mice on the fourth training day. Lower: mean latencies to escape from the water onto the hidden platform on the fourth training day. (E) Upper: typical swimming-tracking path of of vehicle control, Aβ1-42 oligomers-treated mice, bis(heptyl)-cognitin 0.2 mg/kg plus Aβ1-42 oligomers-treated mice, and tacrine 2 mg/kg plus Aβ1-42 oligomers-treated mice in the probe trial. Lower: the swimming distance in the target quadrant (in which the platform had been placed during the training phase) in the probe trial. (F) Average swimming speed in the probe trial. Data represent means ± SEM. ###p < 0.001 vs. vehicle group; *p < 0.05 and **p < 0.01 vs. Aβ1-42 oligomers-treated group in (B-E) (Tukey’s test).

Mentions: Previous studies have shown that Aβ1-42 oligomers lead to the learning and memory impairments in mice3334. In our study, Morris water maze was used to evaluate spatial memory of mice with administration of Aβ1-42 oligomers by intra-hippocampal infusion (Fig. 8A). In the acquisition trials, typical swimming paths on the fourth training day and quantitative escape latencies indicated that mice treated with Aβ1-42 oligomers took longer time to find the platform than did the vehicle-treated mice (p < 0.01, Fig. 8D). This prolongation of latency was significantly shortened by bis(heptyl)-cognitin at the concentrations of 0.1 and 0.2 mg/kg, and tacrine at the concentrations of 2 mg/kg (p < 0.01, Fig. 8D). In the probe trials, the swimming distance in the quadrant that had held the hidden platform was used to estimate performance. The swimming distance in the probe quadrant is longer in groups of mice treated with Aβ1-42 oligomers plus bis(heptyl)-cognitin (0.1, 0.2 mg/kg) and Aβ1-42 oligomers plus tacrine (2 mg/kg) than the group of mice treated with Aβ1-42 oligomers alone (p < 0.01, Fig. 8E). Neither Aβ1-42 oligomers nor drugs altered swimming speed (Fig. 8F).


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 prevents the memory deficits induced by intra-hippocampal infusion of Aβ1–42 oligomers in mice (n = 6 for each group).(A) The schedules of animal experiments. (B,C) Mean latencies to escape from the water onto the hidden platform. Each mouse was subjected to two trials per day for 4 consecutive days. (D) Upper: typical swimming-tracking path of vehicle control, Aβ1-42 oligomers-treated mice, bis(heptyl)-cognitin 0.2 mg/kg plus Aβ1-42 oligomers-treated mice, and tacrine 2 mg/kg plus Aβ1-42 oligomers-treated mice on the fourth training day. Lower: mean latencies to escape from the water onto the hidden platform on the fourth training day. (E) Upper: typical swimming-tracking path of of vehicle control, Aβ1-42 oligomers-treated mice, bis(heptyl)-cognitin 0.2 mg/kg plus Aβ1-42 oligomers-treated mice, and tacrine 2 mg/kg plus Aβ1-42 oligomers-treated mice in the probe trial. Lower: the swimming distance in the target quadrant (in which the platform had been placed during the training phase) in the probe trial. (F) Average swimming speed in the probe trial. Data represent means ± SEM. ###p < 0.001 vs. vehicle group; *p < 0.05 and **p < 0.01 vs. Aβ1-42 oligomers-treated group in (B-E) (Tukey’s test).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f8: Bis(heptyl)-cognitin prevents the memory deficits induced by intra-hippocampal infusion of Aβ1–42 oligomers in mice (n = 6 for each group).(A) The schedules of animal experiments. (B,C) Mean latencies to escape from the water onto the hidden platform. Each mouse was subjected to two trials per day for 4 consecutive days. (D) Upper: typical swimming-tracking path of vehicle control, Aβ1-42 oligomers-treated mice, bis(heptyl)-cognitin 0.2 mg/kg plus Aβ1-42 oligomers-treated mice, and tacrine 2 mg/kg plus Aβ1-42 oligomers-treated mice on the fourth training day. Lower: mean latencies to escape from the water onto the hidden platform on the fourth training day. (E) Upper: typical swimming-tracking path of of vehicle control, Aβ1-42 oligomers-treated mice, bis(heptyl)-cognitin 0.2 mg/kg plus Aβ1-42 oligomers-treated mice, and tacrine 2 mg/kg plus Aβ1-42 oligomers-treated mice in the probe trial. Lower: the swimming distance in the target quadrant (in which the platform had been placed during the training phase) in the probe trial. (F) Average swimming speed in the probe trial. Data represent means ± SEM. ###p < 0.001 vs. vehicle group; *p < 0.05 and **p < 0.01 vs. Aβ1-42 oligomers-treated group in (B-E) (Tukey’s test).
Mentions: Previous studies have shown that Aβ1-42 oligomers lead to the learning and memory impairments in mice3334. In our study, Morris water maze was used to evaluate spatial memory of mice with administration of Aβ1-42 oligomers by intra-hippocampal infusion (Fig. 8A). In the acquisition trials, typical swimming paths on the fourth training day and quantitative escape latencies indicated that mice treated with Aβ1-42 oligomers took longer time to find the platform than did the vehicle-treated mice (p < 0.01, Fig. 8D). This prolongation of latency was significantly shortened by bis(heptyl)-cognitin at the concentrations of 0.1 and 0.2 mg/kg, and tacrine at the concentrations of 2 mg/kg (p < 0.01, Fig. 8D). In the probe trials, the swimming distance in the quadrant that had held the hidden platform was used to estimate performance. The swimming distance in the probe quadrant is longer in groups of mice treated with Aβ1-42 oligomers plus bis(heptyl)-cognitin (0.1, 0.2 mg/kg) and Aβ1-42 oligomers plus tacrine (2 mg/kg) than the group of mice treated with Aβ1-42 oligomers alone (p < 0.01, Fig. 8E). Neither Aβ1-42 oligomers nor drugs altered swimming speed (Fig. 8F).

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