Blueberry extracts antagonize Aβ_25–35 neurotoxicity and exert a neuroprotective effect through MEK-ERK-BDNF/UCH-L1 signaling pathway in rat and mouse hippocampus

ABSTRACT

Background

The neuroprotective potential of blueberry (BB) extracts against Alzheimer's disease (AD) has been previously hinted at, while its exact mechanism has remained largely enigmatic.

Objective

Our study endeavored to unravel the impacts and mechanisms by which BB extracts ameliorated the learning and memory prowess of AD-afflicted mice, with a specific focus on the MEK-ERK pathway.

Methods

We employed 3-month-old APP/PS1 transgenic mice and stratified them into three distinct groups: AD+BB, AD, and control (CT). The Morris Water Maze Test (MWMT) was then administered to gauge their learning and memory faculties. In vitro experiments were executed on Aβ25-35-afflicted rat hippocampal neurons, which were subsequently treated with varying concentrations of BB extracts. We then assessed the expression levels of genes and proteins integral to the MEK-ERKBDNF/UCH-L1 pathway.

Results

The data showed that the AD mice demonstrated compromised learning and memory faculties in MWMT. However, the AD+BB cohort showcased marked improvements in performance. Furthermore, in the AD subset, significant elevations in the expressions of MEK2 and ERK1/2 were observed, both at the mRNA and protein levels. Conversely, UCH-L1 mRNA expressions exhibited a decline, while BDNF expressions surged significantly. However, post BB extract treatment, the expressions of MEK2 and ERK1/2 were subdued, with UCH-L1 and BDNF mRNA expressions reverting to control levels.

Conclusions

Our findings propounded that BB extracts could offer therapeutic promise for AD by bolstering learning and memory capacities. The unwarranted activation of the MEK-ERK pathway, coupled with the aberrant expressions of BDNF and UCH-L1, might underpin AD's pathogenesis.

KEYWORDS:

• Blueberry extracts
• Alzheimer's disease
• MEK-ERK
• BDNF
• UCH-L1
• APP/PS1 transgenic mice
• Morris Water Maze
• learning and memory

Acknowledgments

Author Contributors

Long Tan and Han Zhang contributed equally to the present work. Long Tan and Han Zhang analyzed data and wrote the paper. Long Tan, Haiqiang Li, and Shoudan Sun conducted experiments and data collection. Yugang Jiang designed the research. Yugang Jiang and Quanjun Lyu revised the paper. All authors have read and approved the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Ethical approval

All experiments in the study were carried out according to the protocols approved by the Tianjin Medical University Animal Care and Use Committee on October 31, 2019, following the practices outlined in the NIH Guide for the Care and Use of Laboratory Animals based on the principles of the Declaration of Helsinki. Every effort has been made to minimize the number of animals used and their suffering.

Data availability statement

The data that support the findings of this study are available from the corresponding author, JYG, upon reasonable request.

Additional information

Funding

This work was supported by National Nature Science Foundation of China: [Grant Numbers 81872606, 14JCZDJC36100, and 82073549].