Bis(propyl)-cognitin Reverses β-amyloid-induced Synaptic Plasticity Impairments And Learning And Memory Deficits

Objective: Bis (propyl)-cognitin (B3C) is a multi-target dimmer prevents Alzheimer’s disease(AD), but its specific mechanism in improving learning and memory is unclear. To explore thetherapeutic potential and neuroprotective mechanisms of bis(propyl)-cognitin(B3C) in Alzheimer’sdisease, we investigated the effects of B3C on high frequency stimulation-induced HFS synapticplasticity activation, β-amyloid-induced synaptic plasticity impairments in hippocampal slices andβ-amyloid-induced learning and memory deficits in AD animals, which further provideexperimental evidence and theoretical basis for the novel drugs of AD development.Methods:1. Electrophysiology: All experiments were carried on the transverse hippocampalslices of the Wistar rats (males, aged3-5weeks).The fresh slices were prepared from the anesthesiarats after decapitating. The prepared slices were incubated in artificial cerebrospinal fluid (artificialcerebrospinal fluid, ACSF) for1h, and continuously superfused in the recording chamber atproperly flowing speed and temperature. An extracellular electrophysiological method was used torecord field excitatory postsynaptic potentials (fEPSP) and long-term potentiation (LTP) in dentategyrus (DG) area of the hippocampus. P-CLAMP10was used to analyze the recordings andcalculate the amplitude of LTP. All experiment data were shown as the mean±S.E.M. ANOVAand Student’s t-tests were used for statistical analysis.2. Ethology: Male ICR mice (25-30g) wereused in our experiments. The stereotaxic apparatus were used to establish AD model by theinjection of Aβ1-42oligomers into DG area of hippocampus. Then, B3C (1.5,2.0,2.5μmol/kg)were injected intraperitoneally (ip) once daily. After two weeks, the animals were performed novelobject recognition task and Morris water maze (MWM) to evaluate the learning and memoryability. During the novel object recognition task, the time of exploring the two identical objects wasfirst recorded. Twenty-four hours later, one of the objects was replaced by a novel object. Theexploring time of the two different objects was recorded thereafter, and the identification objectindex of novel object was calculated. The MWM task included training procedure and probe trials.The escape latency was recorded during the training days, while the percentage of distance and theentries in the target quadrant were analyzed during the probe trials.3. Cytology: Primaryhippocampal neurons were prepared from postnatal1-day-old Wistar rats. At day7in vitro (DIV7), the cultured hippocampal neurons were pre-treated with500nM Aβ1-42oligomers for3h or pre-treated with B3C(0.1,0.5,1.0μM) for2h, and then incubated with500nM Aβ1-42for another3h.The confocal laser scanning microscope was used to investigate the morphology of neurons, andthe Image J was used to analyze the density and length of filopodia.Results:1. B3C enhanced the induction and the maintenance of HFS-induced LTP.2. B3Ccould improve or even reverse the Aβ1-42-mediated inhibition of LTP introduction in a dose-dependent manner.3. B3C significantly prevented the Aβ1-42-induced decrease of discriminationindex in AD animals by using the novel object recognition task.4. B3C significantly decreasedescape latency during the training, and increased swimming distance and entries in the targetquadrant during the probe trials in AD animals by using MWM.5. B3C significantly reversed Aβ1-42-induced decrease of density of filopodia in cultured hippocampal neurons.6. In the presence ofAβ1-42alone or B3C pre-treated with Aβ1-42, there was no significant difference about the density offilopodia among cultured hippocampal neurons.Conclusion:1. B3C reversed Aβ-induced synaptic plasticity impairments and learning andmemory deficits, which strongly suggested that B3C is a potential drug for AD treatment.