Cellular- and systems-level profiling of amyloid-beta effects on circadian timing

Disruption of the circadian timing system has been reported in the preclinical phase of Alzheimer's disease (AD) and is a well-characterized component of mid- and late-stage AD. Given the distributed nature of the body's clock, with a central pacemaker in the suprachiasmatic nucleus (SCN) and peripheral clocks throughout the brain, understanding how AD affects this system has been challenging. To investigate how AD may disrupt circadian physiology, we focused on the amyloid-beta (Aβ) peptide, a key contributor to familial early-onset AD. Using the 5xFAD mouse model and ex vivo single-cell profiling, we examined how Aβ influences clock timing in both SCN neurons and hippocampal neuronal populations. Circadian profiling of 5xFAD mice (4- and 8-months-old) showed only modest changes in key clock timing properties, including a shortening of the SCN rhythm. Interestingly, the mice showed enhanced rates of re-entrainment to changes in the light cycle, suggesting that elevated Aβ levels increase the clock's sensitivity to light. Further, using both in vitro SCN slice explant and dispersed SCN culture models, the exogenous administration of oligomerized Aβ had no significant effect on inherent clock timing capacity. In contrast, the timing properties of cultured hippocampal neurons showed a dose-dependent sensitivity to Aβ. This included an elevated mesor and an increased rhythm amplitude. These findings reveal a divergence in Aβ sensitivity between the central SCN clock and peripheral oscillators. This raises the possibility that circadian disruptions in AD may stem from both the destabilization and decoupling of peripheral oscillators from the SCN's central timing properties. • SCN clock timing properties are largely unaffected in 5xFAD mice • Exogenous Aβ oligomers do not alter SCN clock timing in slice or cultured neurons • Hippocampal neurons exhibit Aβ dose-dependent alterations in clock timing • Data suggest that Aβ could decouple peripheral clocks from the SCN