Time-restricted feeding improves cognitive function in Alzheimer's mice through GCK/NPY/apoptosis pathway.

Abstract

UNLABELLED: Alzheimer's disease (AD) is characterized by progressive cognitive decline, neuronal loss, and circadian disruption. Time-restricted feeding (TRF), a dietary intervention that aligns feeding with circadian rhythms, has shown potential benefits in metabolic and neurodegenerative disorders. MATERIALS AND METHODS: Wild-type and APP/PS1/Tau transgenic mice were divided into two groups: ad libitum and TRF, with food provided from Zeitgeber Time (ZT) 14 to ZT24 for TRF. Cognitive performance was assessed using the Morris water maze, Novel object recognition, and Rotarod tests at 3 months post-treatment. Hippocampal tissue was analyzed by Western blot and quantitative real-time Polymerase Chain Reaction (PCR). Nissl staining was used for hippocampal morphology assessment. The glucokinase (GCK)/neuropeptide Y (NPY)/apoptosis pathway was studied by treating HT22 cells with Aβ and siGCK. RESULTS: TRF reduced food intake and alleviated weight gain, while also improving cognitive function, as evidenced by behavioral tests. Furthermore, TRF decreased the accumulation of p-Tau protein and reduced hippocampal neuronal apoptosis, which was mediated through the restoration of the GCK/NPY pathway. In vitro, silencing GCK in an AD cell model led to a reduction in p-Tau levels, an increase in NPY expression, and a reduction in neuronal apoptosis. Notably, when GCK was silenced in the AD cell model, p-Tau levels and neuronal apoptosis recurred. CONCLUSIONS: Our findings suggest that TRF improves cognitive function and reduces neuronal apoptosis in AD mice by modulating the GCK/NPY pathway. These results highlight TRF as a potential nonpharmacological intervention for AD, offering new insights into its underlying mechanisms.