Glial cells are involved in day–night protein dysregulation in the hippocampus of a mouse model of Alzheimer’s disease

Abstract The hippocampus regulates memory and cognition, both of which are influenced by circadian rhythms. These rhythms also drive time-dependent gene expression in neurons and glial cells, affecting hippocampal function. In Alzheimer’s disease (AD), alterations in these rhythms, contributing to cognitive decline, is little understood. This study examined hippocampal proteomes from 7-month-old wild-type (WT) and 3xTgAD mice at two time points (Zeitgeber 2, ZT2 and ZT14) to detect early pathological changes. In WT mice, 199 proteins (8%) showed diurnal variation, particularly those linked to energy metabolism and neuronal/glial functions. In 3xTgAD mice, this rhythmic variation dropped by half (3.6%), with only five proteins shared across genotypes. Moreover, significant differences in protein expression emerged between WT and 3xTgAD at both time points, notably involving mitochondrial function, oxidative phosphorylation, and ATP production. Functional clustering revealed disrupted bioenergetic pathways, especially affecting complex I of the electron transport chain and astrocytic metabolism. These early alterations suggest a breakdown in daily control of hippocampal energy regulation in AD. The results highlight the critical role of sampling time in research and suggest that circadian disruption in astrocytic and neuronal metabolism may play a central role in AD progression and could inform future chronotherapeutic approaches.