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Formyl peptide receptor 2 antagonist WRW4 ameliorates diabetes-induced cognitive decline in mice
Hiroki Uno1, Takahide Itokazu2, Toshihide Yamashita3
1Department of Molecular Neurosciences, Graduate School of Medicine, Osaka University, Suita, Japan.
Abstract:
Cognitive impairment is a significant complication of diabetes. Although the detailed mechanism remains unclear, prolonged neuroinflammation mediated by microglia is recognized as a key contributor to neural dysfunction. Recent studies have shown that Formyl peptide receptor 1 (FPR1), a G protein-coupled chemoattractant receptor, plays a role in microglial activation and brain pathology. However, the involvement of FPR2, another isoform within the FPR family, in microglial activation and cognitive decline has not yet been explored. In this study, we observed an increased expression of FPR2 in microglia within the hippocampus of type 2 diabetes (db/db) mice. Furthermore, we demonstrated that intracerebroventricular administration of WRW4, a selective FPR2 antagonist, alleviates diabetes-related cognitive decline. Histological analysis revealed that WRW4 treatment mitigates morphological alteration and upregulation of a phagocytic marker (CD68) of the microglia in the hippocampus of db/db mice. These results indicate that FPR2 plays a critical role in inducing diabetes-related microglial phenotype. These findings highlight the therapeutic potential of FPR2 signal inhibition as a novel strategy to mitigate cognitive decline associated with diabetes.
Insights
Formyl peptide receptor 2 (FPR2) contributes to diabetes-related cognitive decline by activating microglia. Inhibiting FPR2 with WRW4 improved cognitive function and reduced microglial changes in diabetic mice.
Area of Science:
- Neuroscience
- Immunology
- Endocrinology
Background:
- Cognitive impairment is a common complication of diabetes, linked to neuroinflammation driven by microglia.
- Formyl peptide receptor 1 (FPR1) is implicated in microglial activation, but the role of FPR2 remains unknown.
Purpose of the Study:
- To investigate the role of Formyl peptide receptor 2 (FPR2) in microglial activation and cognitive decline in type 2 diabetes.
- To explore FPR2 as a potential therapeutic target for diabetes-related cognitive impairment.
Main Methods:
- Examined FPR2 expression in microglia of the hippocampus in type 2 diabetic (db/db) mice.
- Administered a selective FPR2 antagonist (WRW4) intracerebroventricularly.
- Assessed cognitive function and performed histological analysis, including CD68 (a phagocytic marker), in the hippocampus.
Main Results:
- FPR2 expression was elevated in hippocampal microglia of db/db mice.
- WRW4 treatment significantly alleviated diabetes-related cognitive decline.
- WRW4 administration reduced microglial morphological alterations and CD68 upregulation in db/db mice.
Conclusions:
- FPR2 plays a critical role in mediating the diabetes-related microglial phenotype.
- Inhibiting FPR2 signaling represents a promising therapeutic strategy for mitigating cognitive decline in diabetes.
