Alzheimer's disease can leave early signs in the gut, study studies

Alzheimer's disease can leave early signs in the gut, study studies

New imaging technology has exposed hidden gut changes in Alzheimer's, revealing a potential gut-brain connection that could revolutionize early diagnosis and treatment.

Alzheimer's disease affects over 30 million people worldwide, but the factors underlying its etiology remain unclear. Recent research has turned to the gut and examined its potential role in Alzheimer's disease progression. In a study recently published in the journalScience advancesA team of researchers from Italy and France used advanced imaging techniques to examine the gut-brain axis and reveal significant gut changes in three different Alzheimer's mouse models, shedding light on the complex nature of the disease.

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Alzheimer's disease is the most common cause of dementia and is characterized by cognitive decline and brain deterioration. Despite extensive research, its exact causes remain unclear and current treatments offer only limited relief. Recent studies have highlighted the gut-brain axis—the communication pathway that connects gut health and brain function—as a potential contributor to Alzheimer's disease.

The gut microbiome plays a critical role in maintaining overall health and has been linked to cognitive function. While previous research suggests that dysbiosis – an imbalance in gut bacteria – may influence Alzheimer's progression, this particular study focused on structural and cellular changes in the gut rather than microbial composition. There is also evidence that disruptions in gut microbiota can promote inflammation and allow harmful bacteria to reach the brain.

Furthermore, changes in intestinal morphology have been observed in Alzheimer's disease patients and animal models, suggesting a possible link between intestinal health and neurodegeneration.

About the study

The first nanoscale imaging of telocytes in Alzheimer's disease models - the study used nano-XPCT to visualize telocytes, specialized cells involved in tissue repair, in Alzheimer's disease research, indicating their potential role in dysfunction.

With the hope that understanding these interactions between the gut microbiome and the brain may open new avenues for early diagnosis and innovative treatments for Alzheimer's disease, the present study investigated gut alterations in Alzheimer's disease models using advanced imaging techniques, specifically both micro- and nano-three-dimensional (3D) X-ray phase-contrast tomography (XPCT), a breakthrough imaging method capable of high-resolution, non-invasive structural visualization.

The research team examined the intestines of three different mouse models of Alzheimer's disease: APP/PS1 and APP23 mice, which carry human genetic mutations associated with the familial Alzheimer's model, and the SAMP8 model, which mimics sporadic, age-related neurodegeneration. These were compared with healthy controls. The ileum, a section of the small intestine, was chosen because of its previously observed involvement in Alzheimer's disease pathology.

The XPCT method enabled non-invasive, high-resolution, three-dimensional imaging that reveals intricate details of intestinal structures without requiring tissue staining or sectioning. Different resolutions were used to capture detailed anatomical structures from the cell to the entire organ level. Additionally, the imaging process involved thousands of projections, which were then reconstructed into 3D volumes for analysis. This approach enabled visualization of intestinal features such as villi, cryptions and various cell types including Paneth and Goblet cells.

In addition, this study was among the first to use XPCT to identify changes in telocytes, a type of interstitial cell involved in tissue repair, suggesting disruptions in intestinal homeostasis in Alzheimer's disease. The XPCT also allowed identification of components of the enteric nervous system such as the myenteric and submucosal plexuses. In addition, the study provided new insights into immune responses in Alzheimer's disease by examining Peyer's spots and isolated lymphoid follicles, essential lymphoid tissues involved in immune surveillance.

Nano-XPCT analysis of Paneth and goblet cells. (A) Representative 3D rendering of the longitudinal view of a SAMR1 mouse crypt. The epithelial layer of the crypt was rendered green. The Paneth cells are colored yellow and the goblet cells are colored blue. Scale bar, 5 μm. (b) And (C) Show 3D renderings and nano-XPCT close-ups of Goblet and Paneth cells. The same color code from (a) was used for the 3D renderings shown in (b) and (c). In detail, the goblet cell nucleus is colored in dark blue and the apical part, which is expanded with mucin-secreting granules extending into the intestinal lumen, is rendered in light blue. The Paneth cell shows the typical pyramidal shape with a basally located nucleus (blue) and prominent apical granules (yellow) that occupy most of its cytoplasmic region. Nano-XPCT close-up images in (b) show goblet cells (indicated by arrows) secreting mucus (asterisks) in the intestinal lumen. Scale bar, 2.5 μm. In (c) transverse view of a crypt in which the Paneth cells are arranged in a radial pattern (highlighted by the dashed line boxes). The release of the antimicrobial granules (black dots, star) into the lumen is visible. Scale bar, 5 μm. (DAndE) Quantification of goblet and Paneth cells in the cryptions. Results are obtained on 30 crypts per mouse (n = 1) and are presented as mean ± SD. One-way ANOVA P < 0.0001; Post hoc according to Tukey's post hoc test: *P < 0.02, ** p < 0.01, *** p < 0.001 and **** p < 0.0001.

Findings and implications

Differences between familial and sporadic Alzheimer's models - The study found that APP/PS1 and APP23 models (familial AD) had more severe intestinal changes than the Samp8 model (sporadic AD), suggesting genetic influences on intestinal structure in Alzheimer's disease.

The study found that Alzheimer's disease is associated with significant structural changes in the intestines. Advanced imaging showed changes in the intestinal villi and crypts, which are crucial structures for nutrient absorption and immune response.

In mouse models of Alzheimer's disease, villi appeared to be deeper compared to healthy controls, indicating disrupted intestinal architecture. In addition, the intestinal epithelial barrier was significantly thinner, which the researchers believe may potentially compromise the intestinal protective functions and increase permeability.

In addition, the abundance of Paneth and goblet cells, which play a role in immune defense and mucus secretion, was particularly altered in Alzheimer's models. An increase in these cells has also been demonstrated along with increased mucus release, indicating a response to inflammatory conditions in the intestine. These results are consistent with previous observations that intestinal dysfunction in Alzheimer's disease may involve an inflammatory component.

The study also identified changes in the enteric nervous system, with changes in neuron structure that may affect gut motility and signaling to the brain. Furthermore, the morphology and number of telocytes were altered, indicating impairments in intestinal repair mechanisms.

In addition, the study found significant changes in Peyer's spots and isolated lymphoid follicles, which are crucial for intestinal immune surveillance, indicating that Alzheimer's disease can produce an increased immune response within the intestine.

Conclusions

Overall, research showed that Alzheimer's disease affects not only the brain, but also the structural integrity and immune function of the gut. This study highlighted the potential link between gut changes and Alzheimer's disease and the importance of gut health in neurodegenerative diseases.

By revealing structural changes and immune responses in the gut, researchers suggested that these changes could serve as early biomarkers of Alzheimer's disease. Understanding these gut-brain interactions could lead to innovative treatments aimed at mitigating the progression of Alzheimer's and further emphasizing the importance of holistic approaches to managing complex neurological diseases.

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