ABSTRACT While mounting evidence points to a potential link between industrial aluminum exposure and neurodegenerative diseases like Alzheimer's disease (AD), the precise intervention strategies remain an area of active research. This study proposes a “multi‐target synergy and dose threshold control” exploratory framework for evaluating Idesia polycarpa crude oil (IPCO) in an aluminum‐induced AD model. An integrated analytical approach employing GC–MS and network pharmacology was used to identify three candidate core components—(Z,Z)‐9,12‐octadecadienoic acid, Beta‐amyrin, and 2,4‐di‐tert‐butylphenol—that were computationally predicted to influence a network of 35 ad ‐related pathways (e.g., Calcium and PPAR signaling) via eight potential key targets (including PTGS2 , PPARG , and AKT1 ). In vivo experiments revealed a dose‐dependent modulation of AD‐related pathology following IPCO intervention. The high‐dose group showed the most marked improvements in several therapeutic markers, including reduced aluminum load, an anti‐inflammatory shift in cytokine levels (elevated IL‐10, decreased IL‐4, IL‐6, IL‐1β, and TNF‐α), and remodeling of the gut microbiota characterized by an increase in putative short‐chain fatty acid (SCFA)‐producing genera such as the Eubacterium‐xylanophilum‐group and NK4A214‐group ( Firmicutes ). Paradoxically, this same high dose was associated with a decline in spatial cognitive performance. This biphasic effect may be preliminarily explained by a dual microbial mechanism: the inhibition of the pro‐inflammatory associated Eubacterium‐oxidoreducens‐group alongside the expansion of taxa linked to a neuroprotective SCFA metabolic network. As one of the first studies to map these multi‐dimensional “constituent–microbiota–neuroinflammation” interactions for IPCO, our findings highlight its complex, dose‐sensitive bioactivity. Importantly, they underscore the critical need for subsequent pharmacokinetic and direct target engagement studies.
Chang et al. (Wed,) studied this question.