Amyloid-β-Induced Changes in Molecular Clock Properties and Cellular Bioenergetics

Area of Science:

• Neuroscience
• Chronobiology
• Molecular Biology

Background:

• Aging impairs the circadian system, increasing susceptibility to age-related diseases like Alzheimer's disease (AD).
• Disrupted sleep and circadian rhythms are early signs of AD, alongside amyloid-beta (Aβ) protein toxicity.
• The role of Aβ in circadian clock abnormalities and bioenergetic imbalance in AD remains unclear.

Purpose of the Study:

• To investigate if Aβ contributes to molecular circadian clock dysfunction.
• To determine if Aβ causes bioenergetic imbalance in cellular models.
• To elucidate the mechanisms linking Aβ, circadian disruption, and metabolic deficits in AD.

Main Methods:

• Utilized human skin fibroblasts, human glioma cells (A172), and mouse primary cortical/hippocampal neurons as oscillator cellular models.
• Assessed circadian period length in response to various amyloid-beta (Aβ) species, including Aβ_1-42 and control peptide Aβ_42-1.
• Examined cellular metabolic state, including ATP levels and mitochondrial respiration, in human primary skin fibroblasts under Aβ_1-42 treatment.

Main Results:

• Physiologically relevant concentrations of Aβ_1-42 (10–500 nM) significantly increased the circadian period length in all tested cell types.
• The control peptide Aβ_42-1 did not affect circadian period length, indicating specificity of Aβ_1-42 action.
• Aβ_1-42 treatment dampened circadian oscillations of ATP levels and mitochondrial respiration, while also increasing the cellular oxidized state.

Conclusions:

• Aβ_1-42 directly impairs the molecular circadian clock, leading to prolonged circadian periods.
• Aβ_1-42 disrupts cellular energy metabolism by dampening oscillations in ATP production and mitochondrial respiration.
• These findings reveal a detrimental cycle of Aβ-induced circadian rhythm decay and metabolic deficits, potentially contributing to Alzheimer's disease pathogenesis.