Research articleDMTHB ameliorates memory impairment in Alzheimer's disease mice through regulation of neuroinflammation
Introduction
Alzheimer Disease (AD) is one of the biggest health care challenges of the 21st century [1]. AD is a neurodegenerative disease characterized by two neuropathological hallmarks: extracellular deposition of amyloid plaques (Aβ) and intracellular neurofibrillary tangles (NFT) [2]. AD is a multi-factorial disease which is the result of interaction between genetic and environmental factors [3]. Within the last decade, neuroinflammation has shown to play a significant role in Alzheimer's disease (AD) [4], [5]. Much of knowledge regarding neuroinflammation is related to the pro-inflammatory cytokines, such as TNF-α, IL-1β and others, which are classically released by infiltrating immune cells within CNS during inflammatory CNS disorders [6], [7].
NLRP3 inflammasome plays an important role in multiple diseases, and it is closely related to inflammatory diseases, such as AD and neuroinflammation [8], [9], [10]. Both studies based on clinical data and animal experiments have found that Aβ deposits can cause NLRP3 inflammasome activation and IL-1β expression is elevated in AD [11], [12]. However, excessive IL-1β levels or chronic IL-1β production can result chronic inflammation of the central nervous system [10]. In addition, some studies have found that IL-1β can induce the phosphorylation of tau protein in the cortex of AD rats [13], [14]. NLRP3 inflammasome inhibitors can significantly reduce the expression of IL-1β and reduce the accumulation of Aβ in brain tissue [15], [16], [17]. In addition, inhibiting NLRP3 can significantly inhibit nervous tangles and nerve plaques, and improve cognitive behavioral disorders in AD [18], [19]. NLRP3 inhibitors may become potential molecular targets for improving AD-related symptoms and slowing down the progression of AD at the level of neuroinflammation [20].
The currently approved treatments for AD are limited to cholinesterase inhibitors and memantine or the combination of these agents [21]. Therapies targeting amyloid β have been the focus for almost 30 years [22]. However, highly promising drugs recently failed to show clinical benefits in phase III trials. Currently, most anti-Tau agents in clinical trials are immunotherapies and they are in the early stages of clinical research [22]. The high failure rate of the therapies in development for AD stems in large part from the complex pathologic causes of the disease, as well as our incomplete understanding of the relationships among the numerous pathways involved in development of AD and subsequent neurodegeneration [23]. Thus, it has been a priority to develop new drug with the potential to change the progression of the disease.
Demethylenetetrahydroberberine (DMTHB) is a derivative of natural medicine berberine and is synthesized from the demethylenation and reduction of berberine in our lab. It has demonstrated that oral bioavailability and biosafety of demethylenetetrahydroberberine (DMTHB) were higher than its precursors of berberine (BBR) and demethyleneberberine (DMB) [24]. It has also been reported that the anti-inflammatory and antioxidant activities of DMTHB were stronger than BBR and DMB [24]. The modulation of inflammatory response and amelioration of oxidative stress confer an advantage to the prevention and treatment of AD [25]. These findings may provide new potential therapeutic agent for the treatment of AD in the future.
Section snippets
Materials
DMEM medium was purchased from Gibco Life Technologies (Grand Island, NY, USA). Fetal bovine serum was purchased from Gibco Life Technologies (Grand Island, NY, USA). Aβ25–35 was purchased from GL Biochem Ltd. (Shanghai, China). Aβ25–35 peptide was dissolved in distilled water at the concentration of 1 mg/ml, filtered to remove bacteria and incubated at 37 °C for 4 days to form aggregated Aβ25–35 peptide. DMTHB was synthesized in our laboratory [24], [26].
Animals
C57BL/6 mice (8 weeks) were purchased
DMTHB improves learning and memory in AD mice induced by Aβ25–35
The Morris water maze (MWM) is a classic experiment for behavioral assessments of the spatial learning and memory abilities of mice [28]. Mice from each group were subjected once daily to the MWM for a total of 6 days. Mice of model group had longer latency (about 41 s), which indicated that the spatial learning and memory of mice are significant decline. Meanwhile, the escape latency of the DMTHB treatment group was significantly improved compared with the model group. (Fig. 2A and B).
Discussion
Alzheimer’s disease (AD) is a chronic neurodegenerative disease that is characterized by progressive memory loss and cognitive disorder [33]. Inflammation processes and cytokines play an important role in pathogenesis of AD. Damaged tissues and β-amyloid plaque are the main inflammation irritants in Alzheimer’s patient brain [34]. In this study, it has been shown that DMTHB ameliorates memory impairment in Alzheimer's disease mice through inhibition of NLRP3 inflammasomes to reduce
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
The authors would like to thank members of laboratory for helpful discussions throughout the project.
Authors' contributions
YQ Z and YB Z designed the project and experiments; YQ Z, DQ L, J W, YH W and XT Y performed experiments; YQ Z and DQ L analyzed results of experiments. YQ Z and YB Z wrote the manuscript with valuable inputs from all the co-authors. All authors read and approved the final manuscript.
Funding
This work was financially supported by National Natural Science Foundation of China (No. 81573484), Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX17_0705), Opening Project of Shanghai Key Laboratory of Complex Prescription (Shanghai University of Traditional Chinese Medicine) (14DZ2271000), and a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).
Availability of data and materials
All data generated and materials supporting the conclusion of the study are included within the article and its Supplementary information files.
Declarations
Ethics approval and consent to participate.
All procedures were approved by the Institutional Animal Care and Use Committee at China Pharmaceutical University and adhered to the Jiangsu Provincial Guidelines for the use of experimental animals.
Consent for publication
Not applicable.
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