Injection of amyloid-β to lateral ventricle induces gut microbiota dysbiosis in association with inhibition of cholinergic anti-inflammatory pathways in Alzheimer's disease

Abstract

Background: Alzheimer's disease (AD) is the most common neurodegenerative disease and its pathogenesis is still unclear. There is dysbiosis of gut microbiota in AD patients. More importantly, dysbiosis of the gut microbiota has been observed not only in AD patients, but also in patients with mild cognitive impairment (MCI). However, the mechanism of gut microbiota dysbiosis in AD is poorly understood. Cholinergic anti-inflammatory pathway is an important pathway for the central nervous system (CNS) regulation of peripheral immune homeostasis, especially in the gut. Therefore, we speculated that dysfunction of cholinergic anti-inflammatory pathway is a potential pathway for dysbiosis of the gut microbiota in AD.

Methods: In this study, we constructed AD model mice by injecting Aβ_1-42 into the lateral ventricle, and detected the cognitive level of mice by the Morris water maze test. In addition, 16S rDNA high-throughput analysis was used to detect the gut microbiota abundance of each group at baseline, 2 weeks and 4 weeks after surgery. Furthermore, immunofluorescence and western blot were used to detect alteration of intestinal structure of mice, cholinergic anti-inflammatory pathway, and APP process of brain and colon in each group.

Results: Aβ_1-42 i.c.v induced cognitive impairment and neuron damage in the brain of mice. At the same time, Aβ_1-42 i.c.v induced alteration of gut microbiota at 4 weeks after surgery, while there was no difference at the baseline and 2 weeks after surgery. In addition, changes in colon structure and increased levels of pro-inflammatory factors were detected in Aβ_1-42 treatment group, accompanied by inhibition of cholinergic anti-inflammatory pathways. Amyloidogenic pathways in both the brain and colon were accelerated in Aβ_1-42 treatment group.

Conclusions: The present findings suggested that Aβ in the CNS can induce gut microbiota dysbiosis, alter intestinal structure and accelerate the amyloidogenic pathways, which were related to inhibiting cholinergic anti-inflammatory pathways.

Keywords: Alzheimer’s disease; Aβ; Cholinergic anti-inflammatory pathway; Gut microbiota.