Unveiling Aging and Alzheimer's Disease-Associated Dynamics of LINE1 DNA Content and Protein Expression in Mouse...

Despite the long interspersed nuclear element-1 (LINE1, L1) retrotransposons having been implicated in Alzheimer's disease (AD), a fundamental understanding of the AD-specific lifespan-long trajectory of L1 has been limited. Here, we characterize the content and expression of L1 covering four brain regions (hippocampus, prefrontal cortex, cerebellum, and the rest of brain tissue) of APP/PS1 mice, a murine model of AD, and their wild-type C57BL/6 littermates from 3 to 24 months of age. We report that both L1 content (indicated by DNA copy number) and expression (indicated by protein levels of L1-encoded ORF1 and ORF2) across brain regions had nonlinear, U-shaped associations with age in wild-type and APP/PS1 mice. Compared to age-matched wild-types, APP/PS1 mice constantly have significantly decreased L1 content but increased L1 expression, suggesting L1 differences between wild-type and APP/PS1 mice establish early and remain stable throughout the life course. Strikingly, L1 content and expression in wild-type and APP/PS1 mice are sexually different, depending on age and brain region. The appearance of L1 alteration precedes the onset of β-amyloidosis by 3 months in APP/PS1 mice, and β-amyloidosis is positively correlated with L1 content and expression in males but anti-correlated with L1 content in females of both wild-type and APP/PS1 mice. Overall, this study (i) reveals an unanticipated U-shaped trajectory of L1 content and expression in both normal and pathological aging of mouse brains and (ii) discerns specific changes in L1 content and expression tied to AD neuropathology in a sex-different manner.