Environmental Cadmium Exposure Exacerbates Alzheimer's-like Pathology in a Gut Microbiota-Involved Manner

Cadmium (Cd), a ubiquitous environmental toxicant, poses substantial health risks even at low-dose chronic exposures. In this study, we developed a mouse model with chronic low-dose dietary Cd exposure (100 nM CdCl₂ in drinking water for eight months) to investigate its impacts on cognitive and neuropathological alterations. Behavioral assessments demonstrated that Cd-exposed mice exhibited pronounced deficits in spatial learning, memory retention, and working memory compared with control mice. Histopathological analyses of hippocampus uncovered accelerated Alzheimer's-like neuropathology, marked by elevated β-amyloid plaque immunoreactivity and tau hyperphosphorylation. Concurrently, neuroinflammatory responses were markedly upregulated, shown as astrocytes activation and pro-inflammatory Th17 cell signatures in parenchyma. Brain transcriptomic profiling revealed extracerebral prostaglandin signaling following Cd exposure, a finding consistent with elevated prostaglandins detected in the gut. Crucially, these outcomes were gut microbiota-involved: antibiotic-mediated microbiota depletion attenuated dietary Cd-enhanced cognitive impairments, neuroinflammation, and prostaglandin upregulation, underscoring the critical role of intestinal microbes in mediating Cd neurotoxicity. Furthermore, in vitro co-culture experiments demonstrated that Cd potentiated prostaglandin production in intestinal epithelial cells-an effect amplified by gut bacterial stimuli. This observation suggests a mechanism under which peripheral prostaglandins may contribute to central inflammatory cascades. Together, these findings support a gut-brain mechanism underlying dietary Cd-exacerbated neurodegeneration and highlight gut homeostasis and prostaglandin signaling as promising therapeutic targets for mitigating Cd-associated neurodegenerative disorders.