Age- and ApoE Genotype-Dependent Transcriptomic Responses to O₃ in the Hippocampus of Mice

Alzheimer's disease (AD) is a leading cause of dementia in the elderly, with late-onset AD (LOAD) accounting for 95% of the cases. The etiology underlying LOAD, however, remains unclear. Using a humanized mouse model, we showed previously that exposure to ozone (O₃), a potential environment risk factor, in a cyclic exposure protocol that mimics a human exposure scenario, accelerated AD-like neuropathophysiology in old humanized male ApoE3 (E3) but not ApoE4 (E4) mice. Using RNA sequencing (RNA-seq) techniques, we further demonstrate here that the ApoE genotype has the greatest influence on transcriptional changes, followed by age and O₃ exposure. Notably, AD-related genes were expressed even at baseline and in young mice, but the differences in the expression levels are obvious in old age. Importantly, although both E3 and E4 mice exhibited some AD-related transcriptomic alterations, old E3 mice exposed to O₃, which showed memory impairment, experienced more pronounced disruptions in the expression of genes related to redox balance, neurogenesis, neuroinflammation, and cellular senescence in the hippocampus, compared with O₃-exposed old E4 mice. These results provide new insights into the molecular mechanisms underlying memory loss in O₃-exposed old E3 male mice and emphasize the complexity of interactions between gene, environment, and aging in AD pathophysiology.