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

What was studied?

This original research article investigated gut microbiota dysbiosis in Alzheimer’s disease induced by intracerebroventricular amyloid-β, a focus that aligns with the focus keyphrase amyloid-β gut microbiota dysbiosis. The investigators examined how Aβ1–42 injection into the lateral ventricle alters microbial composition, intestinal structure, inflammatory signaling, and cholinergic anti-inflammatory pathways. By integrating behavioral testing, 16S rRNA sequencing, immunofluorescence, and protein analyses, the study mapped a mechanistic link between central Aβ pathology and downstream gastrointestinal alterations. The work aimed to clarify how brain-derived amyloid triggers peripheral immune imbalance and microbial shifts and whether disrupted vagal cholinergic signaling acts as the conduit between central pathology and gut dysfunction.

Who was studied?

The study used ten-week-old male C57BL/6J mice randomized into control, sham-operated, and Aβ-injected groups. Mice received intracerebroventricular injections of Aβ1–42 oligomers or vehicle, followed by longitudinal fecal sampling at baseline, two weeks, and four weeks. Behavioral assessments, colon tissue analyses, and microbial sequencing were performed after four weeks. The murine model enabled tightly controlled manipulation of central amyloid exposure and detailed evaluation of downstream neural, immune, and microbial responses, creating a precise experimental platform for dissecting mechanisms relevant to early Alzheimer’s disease.

Most important findings

The Aβ-injected mice exhibited significant cognitive impairment and hippocampal neuronal loss on Morris water maze testing and NeuN staining. Microbiome profiles remained unchanged at baseline and two weeks, but by four weeks showed clear dysbiosis, including reduced Alloprevotella, Ruminiclostridium, and Streptococcus, and increased Akkermansia, Rikenella, and Adlercreutzia—microbial shifts previously associated with AD severity and mucosal inflammation. β-diversity plots illustrate the distinct clustering of the Aβ group. Intestinal permeability increased, with disrupted tight-junction protein ZO-1 and CLDN5 staining, shortened colon length, and reduced enteric neurons, as shown through PGP9.5 labeling. Immune analyses (page 10) revealed a pro-inflammatory shift marked by elevated TNF-α, IL-1β, and IL-6, reduced IL-10, increased CD86, and decreased CD206. Crucially, Aβ suppressed the cholinergic anti-inflammatory pathway: brain M1 acetylcholine receptor expression declined, CHAT levels in the colon dropped, and α7nAChR signaling remained insufficient to counterbalance inflammation. Finally, amyloidogenic pathways were upregulated in both brain and colon, with increased BACE1 in the brain and elevated p-APP and PS1 in the gut.

Key implications

These findings suggest that central amyloid-β pathology is sufficient to induce gut microbiota dysbiosis, intestinal barrier breakdown, and heightened inflammation through suppression of vagal cholinergic anti-inflammatory signaling. The gut becomes both a victim and potential amplifier of AD pathology: local amyloidogenic activity increases, the enteric nervous system is compromised, and microbial imbalance may further influence neuroinflammation. For clinicians, this underscores the gut as a relevant therapeutic target in early AD and reinforces the mechanistic plausibility of interventions such as vagal stimulation, microbiota-directed therapies, and strategies that enhance cholinergic anti-inflammatory tone.

Citation

Qian X, Liu X, Chen G, Chen S, Tang H. Injection of amyloid-β to lateral ventricle induces gut microbiota dysbiosis in association with inhibition of cholinergic anti-inflammatory pathways in Alzheimer’s disease.Journal of Neuroinflammation. 2022;19:236. doi:10.1186/s12974-022-02599-4