Dysbiosis of gut microbiota synergizes with the activation of enteric glial cells to promote Alzheimer's disease

Abstract

Background

The microbiota-gut-brain axis (MGBA) plays a crucial role in the onset and progression of Alzheimer's disease (AD). Enteric glial cells (EGCs) represent a fundamental cellular constituent that upholds the structural and functional integrity of the MGBA. However, the specific mechanistic role of EGCs in the pathogenesis of AD remains unclear.

Objective

The present study aimed to investigate the synergistic interaction between gut microbiota (GM) dysbiosis and EGCs activation in a mouse of AD.

Methods

Amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic AD mice were utilized as the experimental model. Behavioral experiments, 16S rRNA sequencing, Nissl staining, and immunofluorescence staining were used to evaluate the related changes of AD in cognitive function, neuropathology, GM, and EGCs, respectively.

Results

AD mice exhibited significant cognitive dysfunction, with obvious neuronal damage and Aβ plaques formation in the hippocampus and primary somatosensory cortex. The GM composition of AD mice was significantly altered, α-diversity decreased, and the dominant bacterial population was significantly different from the control group. Morphologically, EGCs in the myenteric plexus (MP) and submucosal plexus (SP) of AD mice were markedly activated, concomitant with a reduction in neuronal count. This alteration in EGCs-neuron interactions was shown to be region-specific in MP and SP.

Conclusions

This study confirms characteristic alterations in GM and abnormal EGCs activation in AD mice, while also uncovering regional specificity of these changes within the enteric nervous system. These findings may provide experimental evidence for the development of targeted intervention strategies for AD based on GM and EGCs.