Alzheimer’s disease (AD), which occupies more than 60% in senile dementia, is a kind of neurodegenerative disease characterized by cognitive and memorial deficits. The pathological mechanisms of AD include oxidative stress, neuroinflammation, and especially decreased content of acetylcholine (ACh) in hippocampus (Nuzzo et al., 2022). ACh is closely related to learning and memory ability, its content decreases with age. It is also closely associated with the occurrence of AD, a significant decrease in the content of ACh can be observed in the brain of AD patients (Revi, 2020). The content of ACh is maintained by acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and choline acetyltransferase (ChAT) (Bekdash, 2021). Amyloid plaque deposition, which is one of the diagnostic criteria for AD, can induce oxidative stress and decrease the content of antioxidant enzymes in the brain of patients with AD (Hilt et al., 2018). Nuclear factor erythroid 2-related factor 2 (Nrf2), which is a receptor and regulator of reactive oxygen species (ROS) levels in cells, controls the expression of phase II detoxification enzymes, such as heme oxygenase-1 (HO-1) (Lee and Jeong, 2016). In a mouse model of AD, the Nrf2 pathway is inhibited, and the activation of the Nrf2 pathway effectively alleviates AD (Xu et al., 2020). In addition, amyloid plaque deposition can also activate the immune cells, thereby causing an inflammatory response, promoting the secretion and release of proinflammatory factors (Rajesh and Kanneganti, 2022). Scopolamine (SCP) is an antagonist of M-cholinergic receptor, which antagonizes the effects of ACh by competitively binding to the cholinergic receptor. It can cause damage to cholinergic neurons and induce cognitive dysfunction, and is commonly used in the study of cognitive function in AD (Shen et al., 2020).

The gut microbiota is an important regulatory factor for human health. The homeostasis of microorganisms is crucial for the development and health of the host. The changes in gut microbiota can promote metabolic disorders, leading to the occurrence of AD, which is regulated by the “microbiota-gut-brain axis” (Fung et al., 2017). In scopolamine-induced mice, when the cognitive function was impaired, the composition of gut microbiota was altered (Su et al., 2018). The therapeutic effects of anchovy hydrolysates on AD are partially due to the regulation of the gut microbiota-fecal metabolite-brain neurotransmitter axis (Zhao et al., 2022). At present, gut microbiota is an important target for the treatment of AD (Pistollato et al., 2016). However, whether macamide can improve the structure of gut microbiota is still unknown.

Macamides are considered as unique ingredients in maca (Lepidium meyenii) (Mccollom et al., 2005), exerting various biological activities, such as anti-oxidative (Yu et al., 2019, 2020a), anti-fatigue (Yang et al., 2016), anti-osteoporotic (Liu et al., 2015; Wang et al., 2019), and especially neuroprotective activities (Zhou et al., 2017; Gugnani et al., 2018; Yu et al., 2020b, 2021). Although macamides possess neuroprotective effects, whether they can improve scopolamine-induced cognitive impairment has not been elucidated. In this study, Vina 1.1.2 was used for docking to evaluate the binding abilities of 12 main macamides to AChE. In addition, the mechanisms of N-benzyl-(9Z,12Z)-octadecadienamide (M 18:2) in improving cognitive impairment are studied using a scopolamine-induced mouse neural injury model. Moreover, 16S rRNA sequence was used to study the effect of M 18:2 on gut microbiota.