Maternal cadmium exposure promotes amyloid-beta pathology by interrupting the interaction of AQP1 and HCN1 in male offspring.

Maternal cadmium (Cd) exposure induces Alzheimer's disease (AD)-like cognitive decline in male offspring, yet the precise mechanisms remain poorly understood. Proteomic analysis identified AQP1 as a key protein in the hippocampus of male offspring rats exposed to maternal Cd. Although AQP1 has been implicated in AD pathogenesis, its role in maternal Cd-induced cognitive decline remains unexplored. In this study, we observed dynamic expression patterns of AQP1: upregulation in hippocampal neurons of male offspring rats at postnatal days (PND) 21, 35 and 56, but downregulated in the aged (22-month-old) offspring. Neuronal-specific overexpression of AQP1 significantly reduced Aβ deposition, enhanced synapse-associated protein expression, and improved learning and memory in AD mice. Conversely, AQP1 knockdown exacerbated intracellular Aβ aggregation and suppressed neuronal growth. Further mechanistic studies revealed that AQP1 interacts with hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1), specifically via AQP11-231 and HCN11-401 domains, to facilitate Aβ clearance. Maternal Cd exposure consistently downregulated HCN1 throughout the entire life cycle of male offspring rats, disrupting the AQP1-HCN1 interaction and failing to alleviate Aβ deposition in male offspring rats. HCN1 overexpression rescued AQP1-mediated Aβ clearance despite Cd exposure. In conclusion, our study reveals a novel interaction between AQP1 and HCN1 that is critical for alleviating Aβ pathology and cognitive deficits induced by Cd exposure. These findings highlight potential therapeutic targets and underscore the necessity of controlling environmental Cd levels to mitigate neurodegenerative diseases.