Tacrine accelerates spatial long-term memory via improving impaired neural oscillations and modulating GAD isomers including neuro-receptors in the hippocampus of APP/PS1 AD mice
Introduction
Alzheimer’s disease (AD) is an age-related, progressive, and irreversible neurodegenerative disorder (Hardy, 2006). This is characterized by continuous loss of cognitive functions and the dysfunctions of neuronal network activities leading to the abnormal pattern of neural oscillations towards memory impairment (Gurevicius et al., 2013; Palop et al., 2007). It is estimated that more than 18 million peoples presently suffer from Alzheimer’s (AD), and the number is predicted to sharply increases up to 70 million by 2050 (Chen et al., 2017). Pathology of Alzheimer’s disease is the multiplex platforms towards the dysfunctions that caused neurodegeneration. These multiplex platforms are further underlined by the fact of the low level of acetylcholine, cholinergic neurons, b-amyloid deposits (Barnham et al., 2004; Tapia-Arancibia et al., 2008). In addition to this, cell cycle hypothesis through pre mRNA (UNsnRNA), apoptosis, microglia inflammations, oxidative stress, free radical formation and necrotrophic including tau-protein aggregation are also linked to pathology of AD in the recent era (Cheng et al., 2017; Wang et al., 2015; Karran et al., 2011). Recovery of cholinergic-based AD pathology caused depletion of the declined memory and cognition dysfunction. Cholinesterase inhibitor has been considered as the utmost way to cure the Alzheimer’s patient by improving the acetylcholine (Holzgrabe et al., 2007) science past few years.
In the super medicinal era until now, hindrance and medication of AD are remained tricky. Tacrine is a dose effective drug for cognitive disorder. The rate of its improving and effective treatment in AD disease is not fully explored. However, still work has to be done about the fully effective dose with the risk free rate (Winker, 1994). Therefore, in our study, we used a new small dosage that is 0.5 mg of tacrine /100 g of body weight for the treatment of Alzheimer’s disease in the APP/PS1 AD mice. APP/PS1 is a double transgenic and chimeric AD model mouse containing a mutant human PS1-dE9 and humanized Mo/HuAPP695 s by which it expresses human A-beta proteins. Tacrine is a U.S FDA approved acetylcholine esterase inhibitor, which was recommended as a safe and manageable compound in clinical practice for AD (Crismon, 1994; Kurz, 1998). Further tacrine assists to enhance the amount of acetylcholine among the synaptic junctions of neurons. The less amount of acetylcholine (Ach) was found in the impaired pattern separation-associated spatial memory in AD mice (Zhu et al., 2017; Reddy et al., 2017). Moreover, tacrine was found to improve MWM spatial learning and memory in the albino rat including aged mice (Najafi et al., 2017; Chen et al., 2018). The effect of tacrine on the electrophysiological properties and the activities of neural oscillations are yet not explored.
Nowadays, declined neural oscillations indexes have been becoming the marker of several neurological disorders such as Dementia, Alzheimer’s disease, Epilepsy (Goodman et al., 2018; Zijlmans et al., 2012). Theta-gamma phase-amplitude coupling was altered in the cortico thalamic connections of APPswe/PS1dE9 AD Mice (Gurevicius et al., 2013). In our knowledge, only EEG and local field potentials (LFPs) of septal hippocampal area were analyzed in the APP/PS1 double mutant AD mice. Moreover, this will be the first time when altered electrophysiological properties are represented in the LFP collected from DG area, and from the PP-pathway in REM state of APP/PS1 double mutant humanized AD mice in our current study. DG-area and PP-pathway are very important parts of the hippocampus. They have superior role in the memory formations by the excitation and inhibitions of group of neurons lying in the hippocampus (Aimone et al., 2011; Kumari et al., 2019). Hippocampal oscillatory activities are the early biomarker for the AD pathology (Hamm et al., 2015). Consequently, we raised a next issue that whether tacrine shows influence on neural oscillations including hippocampal long-term synaptic plasticity accompanied with spatial memory.
In the present study, we tried to eliminate the side effect through using our innovative small quantity of drug. Our results admit that tacrine improves the cognitive function during MWM spatial learning and memory. Tacrine further improves the patterns of neural oscillations and its networks leading to improvement in the long-term memory in the hippocampus of APP-PS1 double mutant AD mice. Next, molecular assays were done in order to explore the possible mechanism behind the improving effect of tacrine on the pattern of neural oscillations. The data suggest that tacrine influences the expression of neuron excitatory and synaptic proteins including with the expression of GAD isomers linking to the A-beta changes in the hippocampus of APP/PS1 AD mice.
Section snippets
Experimental animals
The double transgenic APP/PS1 male mice and background matched wild type C57BL/6 mice were purchased from Beijing HFK-Bio-Technology. Co. Ltd. (Beijing china). All mice were housed in animal house, school of medicine, Nankai University. This animal house was kept at 23–25 C having 12 h light /dark cycle. Mice were randomly divided into three groups. CON (n = 6), AD (n = 6), and AD with treatments that is AD-TAC (n = 6). The animal research ethics committee of Medical College, Nankai University
Tacrine improved spatial reference learning and memory
In the present study, the development of spatial learning and memory was tested by the series of Morris Water Maze (MWM) test. Forward, and reverse direction Escape latency were decreased with the increasing of training days (Fig. 1A and B). One-Way Anova indicated that there was a significant change among given groups for the four consecutive training days. (Forward: the 1st day: F(2, 13) = 6.567, P = 0.01, the 2nd day: F(2,13) = 3.981, P = 0.048, the 3rd day: F(2,13) = 4.47, P = 0.027, and
Discussion
Although in past tacrine showed few side effect, it was approved by clinicians and FAD that tacrine could be used clinically for AD with safe and manageable dosages (Crismon, 1994; Kurtz, 1998). Alongside, tacrine improved the acetylcholine level in most brain areas of sectioned 12-month old mice brain. These areas are important for learning and memory including with neuronal network and synaptic plasticity (Vallianatou et al., 2019). Hippocampal memory was improved in the amnesia mice treated
Conclusions
Interestingly, our results suggest that tacrine (0.5 mg/100 g W) is associated with the improvement of spatial learning and memory accompanied by increased activity of neural oscillations, which further improved the source of neurotransmitter, GAD65 isomers, and synaptic protein in the hippocampus. We believe our evidences are intertwined with improvement in spatial long-term memory with the specific pattern right away without having any side effect. We may say this small dosage of tacrine can
Author contributions
E.K., ZY, & T.Z. designed the study; E.K. performed numerical experiments including with molecular experiments; K.L. performed other parts of biological experiments; E.K. & T.Z. wrote the manuscript.
Declaration of Competing Interest
There is not a conflict of interest for all authors.
Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (31771148) and 111 Project (B08011).
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These two authors contributed equally to this work.