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

Area of Science:

• Neuroscience
• Chronobiology
• Molecular Biology

Background:

• Circadian rhythm disruption is an early sign of Alzheimer's disease (AD).
• The brain's clock system involves a central pacemaker (suprachiasmatic nucleus) and peripheral clocks.
• Amyloid-beta (Aβ) peptides are key in AD pathogenesis and may disrupt circadian rhythms.

Purpose of the Study:

• To investigate how Aβ peptides affect circadian clock timing in the suprachiasmatic nucleus (SCN) and hippocampus.
• To determine if Aβ differentially impacts central and peripheral circadian oscillators in AD.

Main Methods:

• Utilized the 5xFAD mouse model for Alzheimer's disease.
• Performed ex vivo single-cell profiling and circadian profiling of SCN and hippocampal neurons.
• Examined the effects of exogenous oligomerized Aβ on cultured SCN and hippocampal neurons.

Main Results:

• 5xFAD mice showed modest changes in SCN rhythm but enhanced re-entrainment to light cycles.
• Oligomerized Aβ did not significantly affect inherent SCN clock timing in vitro.
• Cultured hippocampal neurons exhibited dose-dependent sensitivity to Aβ, with altered mesor and amplitude.

Conclusions:

• Amyloid-beta peptides have differential effects on central (SCN) and peripheral (hippocampal) circadian oscillators.
• AD-related circadian disruptions may arise from destabilized peripheral clocks and their decoupling from the SCN.
• Findings suggest Aβ impacts peripheral clocks more significantly, contributing to overall circadian dysregulation in Alzheimer's disease.