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 Aβ1–42 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 Aβ1–42 i.c.v induced cognitive impairment and neuron damage in the brain of mice. At the same time, Aβ1–42 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 Aβ1–42 treatment group, accompanied by inhibition of cholinergic anti-inflammatory pathways. Amyloidogenic pathways in both the brain and colon were accelerated in Aβ1–42 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.

Multi-omics data reveals aberrant gut microbiota-host glycerophospholipid metabolism in association with neuroinflammation in APP/PS1 mice

“…Immunofluorescence assays were performed as previously described. 8 After washing with PBS, 30 μm mouse brain slices were soaked in PBS containing 0.5% Triton X-100 (PBS-T) for 30 min. The brain slices were then blocked with 10% goat serum and 0.5% Triton X-100 in PBS for 1 h at room temperature.…”

Therapeutics for neurodegenerative diseases by targeting the gut microbiome: from bench to bedside

“…Furthermore, injection of Aβ into the lateral ventricle can cause cognitive impairments and inhibit the vagus nerve-mediated cholinergic anti-inflammatory pathway. This inhibition is accomplished by reducing the expression of M1-type acetylcholine receptors in the mouse brain [ 26 ]. Consequently, it results in decreased acetylcholine secretion and reduced α7 acetylcholine receptor levels in gut macrophages [ 26 ].…”

“…This inhibition is accomplished by reducing the expression of M1-type acetylcholine receptors in the mouse brain [ 26 ]. Consequently, it results in decreased acetylcholine secretion and reduced α7 acetylcholine receptor levels in gut macrophages [ 26 ]. These changes shift the macrophages towards pro-inflammatory phenotypes, ultimately causing damage to enteric neurons and the gut mucosal barrier, and accelerating amyloidogenic pathways and gut microbiome dysbiosis [ 26 ].…”

“…Consequently, it results in decreased acetylcholine secretion and reduced α7 acetylcholine receptor levels in gut macrophages [ 26 ]. These changes shift the macrophages towards pro-inflammatory phenotypes, ultimately causing damage to enteric neurons and the gut mucosal barrier, and accelerating amyloidogenic pathways and gut microbiome dysbiosis [ 26 ]. These data suggest that Aβ in the brain has a direct effect on gut homeostasis and gut microbiome profiles.…”

Exploratory Study of Gastrointestinal Redox Biomarkers in the Presymptomatic and Symptomatic Tg2576 Mouse Model of Familial Alzheimer’s Disease: Phenotypic Correlates and Effects of Chronic Oral d-Galactose

“…Accumulating evidence suggests that the gut might play an important role in the etiopathogenesis and progression of Alzheimer’s disease (AD). , Gastrointestinal (GI) alterations have been reported in both transgenic − and nontransgenic animal models of AD. − Importantly, GI alterations often precede neuropathological changes in the brain and correlate with disease progression, , suggesting that pathophysiological processes in the gut might contribute to dyshomeostasis in the central nervous system (CNS) in the early stages of neurodegeneration. Honarpisheh et al reported that GI dysfunction takes place before the onset of cognitive symptoms and the accumulation of cerebral amyloid-β (Aβ) in the (6 months old) Tg2576 mouse model of familial AD .…”