Sleeve gastrectomy improves cognition by enhancing central ERK/CREB/BDNF pathway through increased GIP secretion

Area of Science:

• Neuroscience
• Endocrinology
• Gastroenterology

Background:

• Alzheimer's disease (AD) involves complex gut-brain axis dysregulation.
• Therapeutic strategies targeting AD pathogenesis are urgently needed.

Purpose of the Study:

• To investigate the effects of sleeve gastrectomy (SG) on cognitive function and AD pathology in a mouse model.
• To explore the role of incretin hormones (GIP and GLP-1) in mediating SG's effects on the gut-brain axis in AD.

Main Methods:

• Utilized APP/PS1/Tau triple transgenic mice and HT22 cells.
• Assessed cognitive performance, anxiety-like behavior, glucose tolerance, and insulin sensitivity.
• Measured neuronal damage, phosphorylated tau (pTau) accumulation, and GIP/GLP-1 levels.
• Investigated the ERK/CREB/BDNF pathway activity and GIP receptor function.

Main Results:

• SG improved cognitive function and reduced anxiety in AD mice without significant body weight changes.
• SG attenuated hippocampal neuronal damage and pTau accumulation.
• Peripheral and hippocampal GIP and GLP-1 levels increased, activating the ERK/CREB/BDNF pathway.
• GIP and GLP-1 signaling synergistically protected against Aβ-induced pTau in HT22 cells.

Conclusions:

• Sleeve gastrectomy ameliorates AD-like pathology and cognitive deficits in mice primarily via enhanced GIP/GLP-1 signaling.
• These findings support targeting the GIP/GLP-1 axis as a potential therapeutic strategy for Alzheimer's disease.