Neuroprotection of macamide in a mouse model of Alzheimer's disease involves Nrf2 signaling pathway and gut microbiota

Nengyin Xia; Lingyun Xu; Mengyuan Huang; Dengrui Xu; Yang Li; Haoming Wu; Zhinan Mei; Zejun Yu

doi:10.1016/j.ejphar.2024.176638

Neuroprotection of macamide in a mouse model of Alzheimer's disease involves Nrf2 signaling pathway and gut microbiota

Eur J Pharmacol. 2024 May 9:975:176638. doi: 10.1016/j.ejphar.2024.176638. Online ahead of print.

Authors

Nengyin Xia¹, Lingyun Xu¹, Mengyuan Huang¹, Dengrui Xu¹, Yang Li¹, Haoming Wu¹, Zhinan Mei², Zejun Yu³

Affiliations

¹ School of Life Science and Technology, Wuhan Polytechnic University, Wuhan, 430023, China.
² College of Plant Science & Technology, Huazhong Agricultural University, Wuhan, 430070, China.
³ School of Life Science and Technology, Wuhan Polytechnic University, Wuhan, 430023, China. Electronic address: yuzejun@whpu.edu.cn.

PMID: 38734297
DOI: 10.1016/j.ejphar.2024.176638

Abstract

The underlying mechanisms of macamide's neuroprotective effects in Alzheimer's disease (AD) were investigated in the paper. Macamides are considered as unique ingredients in maca. Improvement effects and mechanisms of macamide on cognitive impairment have not been revealed. In this study, Vina 1.1.2 was used for docking to evaluate the binding abilities of 12 main macamides to acetylcholinesterase (AChE). N-benzyl-(9Z,12Z)-octadecadienamide (M 18:2) was selected to study the following experiments because it can stably bind to AChE with a strong binding energy. The animal experiments showed that M 18:2 prevented the scopolamine (SCP)-induced cognitive impairment and neurotransmitter disorders, increased the positive rates of Nrf2 and HO-1 in hippocampal CA1, improved the synaptic plasticity by maintaining synaptic morphology and increasing the synapse density. Moreover, the contents of IL-1β, IL-6, and TNF-α in the hippocampus, serum, and colon were reduced by M 18:2. Furthermore, M 18:2 promoted colonic epithelial integrity and partially restored the composition of the gut microbiota to normal, including decreased genera Clostridiales_unclassified and Lachnospiraceae_unclassified, as well as increased genera Muribaculaceae_unclassified, Muribaculum, Alistipes, and Bacteroides, which may be the possible biomarkers of cognitive aging. In summary, M 18:2 exerted neuroprotective effects on SCP-induced AD mice possibly via activating the Nrf2/HO-1 signaling pathway and modulating the gut microbiota.

Keywords: Acetylcholinesterase; Alzheimer’s disease; Gut microbiota; Macamide; Nrf2/HO-1 pathway.