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

## TL;DR

This study shows that ozone exposure affects gene activity in the brains of old mice differently based on their ApoE type and age, offering insights into Alzheimer's disease.

## Contribution

The study reveals how ApoE genotype, age, and ozone exposure interact to influence gene expression in Alzheimer's-related pathways.

## Key findings

- ApoE genotype has the greatest influence on transcriptional changes compared to age and ozone exposure.
- Old E3 mice exposed to ozone show more pronounced disruptions in AD-related genes than old E4 mice.
- Baseline AD-related gene expression is present in young mice but becomes more distinct with age.

## Abstract

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.