TRANSCRIPTIONAL AND EPIGENOMIC PROFILING IN THE ENTORHINAL CORTEX IN AMYLOID AND TAU MOUSE MODELS OF ALZHEIMER’S DISEASE

Although the neuropathological signatures of Alzheimer's disease (AD) have been well characterized, the specific mechanisms involved in the onset and progression of the disease are still unknown. The onset of neuropathology is hypothesized to involve transcriptomic and epigenomic changes in specific regions of the brain, with certain brain regions affected earlier and more severely than others. The entorhinal cortex (ECX), located in the medial temporal lobe and involved in memory formation and recall, shows signs of pathology in the very early stages of AD, including the deposition of beta amyloid plaques and neurofibrillary tangles. In this study we investigated the transcriptional and epigenomic effects of amyloid and tau pathology in the ECX using two well-characterised rodent models of AD neuropathology: the J20 and the rTg4510 mouse lines. The J20 mouse model overexpresses human amyloid precursor protein (APP) with both the Swedish and Indiana mutations, and the rTg4510 mouse model overexpresses a human mutant (P301L) form of the microtubule-associated protein tau (MAPT). We used highly parallel RNA-seq to measure changes in gene expression in transgenic mice compared to wild-type littermate controls at four different ages. Longitudinal changes in gene expression associated with the progression of neuropathology were identified in mutant mice, including at loci previously implicated in amyloid pathology and the immune response. Transcriptional data is currently being integrated with epigenetic and histopathological data in the same animals. These data will identify novel pathways involved in the development of AD-associated neuropathology that will uncover mechanisms associated with the progression of disease. Ultimately, changes identified in mouse models of neuropathology will be compared with data generated with ongoing studies of human AD using extensive datasets generated by our group.