Alterations of Transcriptional Profiles in the 3xTg/Polβ AD mouse model

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. Nuclear and mitochondrial DNA integrity is pivotal for healthy aging. DNA damage and alterations in cellular DNA repair capacity have been implicated in the aging process and in age-associated neurodegenerative diseases, including AD. Previous findings show that the essential DNA base excision repair enzyme DNA polymerase β (Polβ) is reduced in the brain during normal aging and in patients with AD. The role of DNA repair in AD pathogenesis, however, remains unclear, therefore, we generated 3xTg AD mice with reduced Polβ expression (heterozygote). We hypothesized that the lack of base excision DNA repair contributes to neurodegeneration in AD via alterations in transcriptional profiles that contributes to development of AD features. We have previously reported memory and olfactory deficits in our mice. Since the hippocampus and olfactory bulbs are critical for memory and olfaction, respectively, we used microarrays and spatial transcriptomics to interrogate gene expression changes in these regions of our mice. We found AD-associated, mitochondrial, detoxification, and lipid metabolism genes and pathways changed in our mice. Since loss of olfaction is one of the earliest symptoms in AD, elucidation of genes and pathways specifically altered in olfactory bulbs may yield novel genes/pathways that can be used as novel biomarkers.

This research was supported in part by the Intramural research Program of the NIH, National Institute on Aging and Thon Foundation (with Tone Tonjum and Lene Juel Rasmussen).