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

Feb 26, 2026The Journal of nutritional biochemistry

Time-limited eating may improve thinking skills in Alzheimer's mice through sugar metabolism, appetite signals, and cell survival pathways

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Abstract

Time-restricted feeding (TRF) improved cognitive function and reduced weight gain in Alzheimer's disease mice.

TRF reduced food intake and alleviated weight gain in mice.
Cognitive performance improved as indicated by behavioral tests following TRF.
TRF decreased the accumulation of p-Tau protein in the hippocampus.
Neuronal apoptosis in the hippocampus was reduced with TRF.
The effects of TRF on neuronal health and cognition may be linked to the modulation of the GCK/NPY pathway.
In an AD cell model, silencing GCK led to reduced p-Tau levels and decreased neuronal apoptosis.

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BACKGROUND: 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 (AL) and time-restricted feeding (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 PCR. Nissl staining was used for hippocampal morphology assessment. The GCK/NPY/apoptosis pathway was studied by treating HT22 cells with Aβ and siGCK.

RESULTS: Time-restricted feeding 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 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 non-pharmacological intervention for Alzheimer's disease, offering new insights into its underlying mechanisms.

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

Abstract

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