Poster abstracts
Poster number 79 submitted by Nicklaus Halloy
The PS19 mouse model of tauopathy: pathological profiling and circadian timing
Nicklaus Halloy (Neuroscience Graduate Program, The Ohio State University), Megan Formanowicz (Department of Neuroscience, The Ohio State University), Cassie Pham (Department of Neuroscience, The Ohio State University), Kari R. Hoyt (Division of Pharmaceutics & Pharmacology, The Ohio State University), Karl Obrietan (Department of Neuroscience, The Ohio State University)
Abstract:
Circadian disruptions are prevalent in Alzheimer’s disease (AD), and the misfolding and aggregation of tau protein into neurofibrillary tangles—one of the pathological hallmarks of AD—may play an integral role. The suprachiasmatic nucleus (SCN) serves as the principal circadian pacemaker, and recent studies have indicated disruptions in core clock timing properties in AD. However, the mechanism by which SCN clock physiology is disrupted in AD remains to be fully elucidated. Thus, examining potential effects of tau pathology on circadian timing is an area of significant interest. To this end, we performed a histological and functional characterization of the SCN in the PS19 (Prnp-huMAPT*P301S) transgenic mouse model of tauopathy. PS19 mice exhibit age-associated pathological markers, including gliosis and synaptic loss at 3 months of age, neurofibrillary tangles by 6 months, and cell death by 9 months. Immunolabeling of the SCN for phospho-tau (Ser202, Thr205) revealed elevated phospho-tau expression within the SCN at 2 months-of-age, which is very early in the pathological process. To assess the functional output of the SCN, we profiled daily locomotor activity (a measure of SCN timing and phasing) in PS19 and wild-type (WT) mice of both sexes. Data was collected from 3 to 11 months of age, which provides a profile of potential effects that manifest during pathological progression. Despite an increasing number of tau inclusions within and around the SCN up to 11 months-of-age, PS19 mice did not display differences in activity profile, re-entrainment rate, or inherent pacemaker activity. Additionally, no sexually dimorphic differences were observed in any measured circadian parameters. However, PS19 mice exhibited a modest increase in average activity compared to WT mice under constant light conditions, t(14) = 2.66, p = .018. Together, these findings indicate that hyperphosphorylation of tau and pathological tau aggregation within the SCN of PS19 mice are not sufficient to induce changes in core timing properties of the SCN, although, there appears to be a heightened sensitivity to light. Current work is focused on examining the potential effects of tau aggregation on the cellular-level timing properties of the SCN.
Keywords: circadian, tauopathy, SCN