iScienceJun 22, 2026

Sleeve gastrectomy may improve thinking by boosting a brain pathway through higher GIP hormone levels

Gut-Brain Axis Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 23, 2026

Abstract

Sleeve gastrectomy (SG) improved cognitive performance in Alzheimer's disease mice without affecting body weight or food intake.

SG enhanced glucose tolerance and insulin sensitivity in APP/PS1/Tau triple transgenic mice.
Cognitive performance improved significantly, and anxiety-like behavior was reduced following SG.
Neuronal damage and pTau accumulation in the hippocampal CA3 region were attenuated after SG.
SG increased both peripheral levels and hippocampal presence of hormones GIP and GLP-1.
Activation of the ERK/CREB/BDNF pathway was observed alongside the hormonal changes.
Inhibition of the GIP receptor worsened Aβ-induced pTau, while GLP-1 showed a synergistic effect.

Simplified

Sleeve gastrectomy (SG) was used to probe the gut-brain axis in Alzheimer's disease (AD). In APP/PS1/Tau triple transgenic mice, SG improved glucose tolerance and insulin sensitivity without lasting effects on body weight or food intake. SG significantly improved cognitive performance and reduced anxiety-like behavior, attenuated neuronal damage and pTau accumulation in the hippocampal CA3 region, and increased both peripheral levels and hippocampal immunoreactivity of GIP and GLP-1 along with ERK/CREB/BDNF pathway activity. In HT22 cells, GIP receptor knockdown exacerbated Aβ-induced pTau and suppressed this pathway, whereas GLP-1 acted synergistically. These findings indicate that SG could improve cognition in non-obese AD mice largely through GIP/GLP-1 signaling rather than metabolic changes, supporting dual incretin targeting as a therapeutic strategy for AD.