Gastrointestinal Dysfunction and Low-Grade Inflammation Associate With Enteric Neuronal Amyloid-β in a Model for Amyloid Pathology

Abstract

Background Patients suffering from Alzheimer's disease, a progressive neurodegenerative disorder involving cognitive decline and memory impairment, often present with gastrointestinal comorbidities. Accumulating data also indicate that alterations in the gut can modulate Alzheimer's disease pathology, highlighting the need to better understand the link between gastrointestinal abnormalities and neurodegeneration in the brain. Methods To disentangle the pathophysiology of gastrointestinal dysfunction in Alzheimer's disease, we conducted a detailed pathological characterization of the gastrointestinal tract of 5xFAD mice by performing histological analyses, gene expression studies, immunofluorescence labeling and gut function assays. Results We found that 5xFAD mice have elevated levels of intestinal amyloid precursor protein and accumulate amyloid-beta in enteric neurons. Histopathology revealed that this is associated with mild intestinal inflammation and fibrosis and accompanied by increased expression of proinflammatory cytokines. While overall enteric nervous system composition and organization appeared unaffected, 5xFAD mice have faster gastrointestinal transit. Conclusion Our findings indicate that amyloid-beta accumulation in enteric neurons is associated with low-grade intestinal inflammation and altered motility and suggest that peripheral pathology may cause gastrointestinal dysfunction in Alzheimer's disease patients.