Chronic subclinical inflammation, cognitive function, RAGE

Research into the onset and prevention of cognitive impairment in lifestyle-related diseases and diabetes

Using endothelial cells as a setting, we clarified the relationship and mechanism of the inflammatory signal caused by the receptor for advanced glycation end products (RAGE) and its cleavage (Miyoshi A et al. FASEB J 33: 3575-3589, 2019; Figure 1). In recent years, cognitive impairment due to obesity and diabetes has attracted attention. In light of the reports of the involvement of immune cells, brain inflammation, and cerebrovascular inflammation in the pathology of cognitive impairment, this research project adopts a chronic latent inflammation model and a high-fat diet-induced obesity model, and uses the following various genetically modified mice and chimeric mice to aim to obtain knowledge about the involvement of RAGE in peripheral immune cells, brain and cerebrovascular inflammation, latent inflammation, and the significance of cognitive impairment, as well as their control.

• Vascular endothelium-specific human RAGE overexpression mice → Physiology significance of RAGE in vascular endothelium can be investigated
• RAGE-deficient mice: the whole-body effects of RAGE deficiency can be examined
• Chimeric mice: bone marrow from RAGE-deficient mice was transplanted into CD45.1 mice, enabling the effects of RAGE deficiency on immune cells to be examined.
• Microglia and vascular endothelium-specific RAGE-deficient mice → Physiology significance of RAGE in microglia and vascular endothelium can be examined

Clarification of the relationship and mechanism of inflammatory signaling caused by the cleavage of the receptor for advanced glycation end products (RAGE) in vascular endothelial cells

We have conducted clinical and basic research focusing on RAGE and have acquired the necessary know-how and tools.

• Adenovirus-mediated overexpression of human RAGE and esRAGE (in vitro, in vivo)
• RAGE-deficient mice are useful for verifying the in vivo action of RAGE, chimeric mice using bone marrow transplantation, Alzheimer's disease model mice, and specific RAGE-deficient mice using the Cre-loxp system.

Cognitive impairment due to obesity and diabetes is an issue that needs to be resolved and is attracting attention. If this study reveals the involvement of RAGE in peripheral immune cells, as well as inflammation in the brain and cerebrovascular system, subclinical inflammation, and cognitive impairment, it is expected that this will lead to the resolution of the above issues.

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1. Shoji T, Koyama H et al. Diabetes 55:2245-2255, 2006
2. Koyama H, Shoji T et al. Arterioscler Thromb Vasc Biol 27: 147-153, 2007
3. Monden M, Shoji T, Koyama H et al. Diabetes 62:478-489, 2013
4. Miyoshi A, Shoji T, Koyama H et al. FASEB J 33: 3575-3589, 2019