Protection against ?-amyloid-induced synaptic and memory impairments via altering ?-amyloid assembly by bis(heptyl)-cognitin.

ABSTRACT: ?-amyloid (A?) 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 A? oligomers-induced inhibition of long-term potentiation (LTP) at concentrations that did not interfere with normal LTP. Bis(heptyl)-cognitin also prevented A? 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 A? 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 A? assembly via directly inhibiting A? oligomers formation and reducing the amount of preformed A? oligomers. Molecular docking analysis further suggested that bis(heptyl)-cognitin presumably interacted with the hydrophobic pockets of A?, which confers stabilizing powers and assembly alteration effects on A?. Most importantly, bis(heptyl)-cognitin significantly reduced cognitive impairments induced by intra-hippocampal infusion of A? oligomers in mice. These results clearly demonstrated how dimeric agents prevent A? 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.

SUBMITTER: Chang L 

PROVIDER: S-EPMC4508546 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature