Effects of BIS-MEP on Reversing Amyloid Plaque Deposition and Spatial Learning and Memory Impairments in a Mouse Model of β-Amyloid Peptide- and Ibotenic Acid-Induced Alzheimer's Disease.

Hongzhuan Chen,Yu Wang,Rui Zhang,Lina Hou,Yuhuan Shi,Qiong Xie,Zhuibai Qiu,Jianrong Xu,Jia Xia,Yongfang Zhang,Zhe Wu,Yifan Zhou,Mengjun Shen,Hao Wang

doi:10.3389/fnagi.2019.00003

Hongzhuan Chen, Yu Wang + Show 12 more

Open Access

https://doi.org/10.3389/fnagi.2019.00003

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Abstract

Alzheimer’s disease (AD) is the main type of dementia and is characterized by progressive memory loss and a notable decrease in cholinergic neuron activity. As classic drugs currently used in the clinic, acetylcholinesterase inhibitors (AChEIs) restore acetylcholine levels and relieve the symptoms of AD, but are insufficient at delaying the onset of AD. Based on the multi-target-directed ligand (MTDL) strategy, bis-(-)-nor-meptazinol (BIS-MEP) was developed as a multi-target AChEI that mainly targets AChE catalysis and the β-amyloid (Aβ) aggregation process. In this study, we bilaterally injected Aβ oligomers and ibotenic acid (IBO) into the hippocampus of ICR mice and then subcutaneously injected mice with BIS-MEP to investigate its therapeutic effects and underlying mechanisms. According to the results from the Morris water maze test, BIS-MEP significantly improved the spatial learning and memory impairments in AD model mice. Compared with the vehicle control, the BIS-MEP treatment obviously inhibited the AChE activity in the mouse brain, consistent with the findings from the behavioral tests. The BIS-MEP treatment also significantly reduced the Aβ plaque area in both the hippocampus and cortex, suggesting that BIS-MEP represents a direct intervention for AD pathology. Additionally, the immunohistochemistry and ELISA results revealed that microglia (ionized calcium-binding adapter molecule 1, IBA1) and astrocyte (Glial fibrillary acidic protein, GFAP) activation and the secretion of relevant inflammatory factors (TNFα and IL-6) induced by Aβ were decreased by the BIS-MEP treatment. Furthermore, BIS-MEP showed more advantages than donepezil (an approved AChEI) as an Aβ intervention. Based on our findings, BIS-MEP improved spatial learning and memory deficits in AD mice by regulating acetylcholinesterase activity, Aβ deposition and the inflammatory response in the brain.

Highlights

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that slowly destroys memory and cognitive performance in the elderly (De Strooper and Karran, 2016)
The subcutaneous injection of BIS-MEP at both the low dosage (0.2 μg/kg/day) and high dosage (2 μg/kg/day) significantly ameliorated the learning deficits induced by Aβ+ibotenic acid (IBO), as indicated by the decreased escape latency to locate the hidden platform (Figure 2A)
We investigated the efficacy of the multipotent acetylcholinesterase inhibitors (AChEIs) BIS-MEP in classic AD model mice

Summary

Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that slowly destroys memory and cognitive performance in the elderly (De Strooper and Karran, 2016). Acetylcholinesterase inhibitors (AChEIs) can help manage cholinergic neuron recovery and memory loss (Bond et al, 2012; Alzheimer’s Association, 2017). Marketed AChEIs are the mainstream drugs used in the clinic for AD therapy. This intervention may temporarily alleviate symptoms, but rarely exerts long-term effects or slows the pathological process of AD (Pang et al, 1996; Galimberti and Scarpini, 2016). As shown in our previous study, one nor-meptazinol moiety of BIS-MEP participates in a hydrogen bond with histidine 447 in the CAS and hydrophobic interactions with tryptophan 86 to disrupt catalytic triad. The other nor-meptazinol moiety binds to tryptophan 286 in the PAS through cation-π and hydrophobic interactions (Paz et al, 2009). Since BIS-MEP exhibits multi-target therapeutic potential against AD, an assessment of its effects on more integrated AD models is urgently needed

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