Tasnády Kinga Réka, Jehoul Reindert, de Ravé Manuel Gutiérrez, Gijbels Marion J, Brône Bert, Dewachter Ilse, Melotte Veerle, Boesmans Werend
Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium.
Department of Pathology, GROW-Research Institute for Oncology and Reproduction, Maastricht University Medical Centre, Maastricht, the Netherlands.
Neurogastroenterol Motil. 2025 May;37(5):e15016. doi: 10.1111/nmo.15016. Epub 2025 Mar 6.
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.
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.
We found that 5xFAD mice have elevated levels of intestinal amyloid precursor protein and accumulate amyloid-β 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.
Our findings indicate that amyloid-β 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.
患有阿尔茨海默病的患者，这是一种涉及认知衰退和记忆障碍的进行性神经退行性疾病，常伴有胃肠道合并症。越来越多的数据还表明，肠道的改变可调节阿尔茨海默病的病理过程，凸显了更好地理解胃肠道异常与大脑神经退行性变之间联系的必要性。
为了阐明阿尔茨海默病中胃肠功能障碍的病理生理学，我们通过进行组织学分析、基因表达研究、免疫荧光标记和肠道功能检测，对5xFAD小鼠的胃肠道进行了详细的病理特征分析。
我们发现5xFAD小鼠肠道淀粉样前体蛋白水平升高，且在肠神经元中积累淀粉样β蛋白。组织病理学显示，这与轻度肠道炎症和纤维化有关，并伴有促炎细胞因子表达增加。虽然整体肠神经系统的组成和结构似乎未受影响，但5xFAD小鼠的胃肠转运速度更快。
我们的研究结果表明，肠神经元中淀粉样β蛋白的积累与低度肠道炎症和运动改变有关，并提示外周病理学可能导致阿尔茨海默病患者出现胃肠功能障碍。
