Targeting the RAGE-RIPK1 binding site attenuates diabetes-associated cognitive deficits

Area of Science:

• Neuroscience
• Immunology
• Endocrinology

Background:

• Microglial activation drives neuroinflammation, contributing to cognitive deficits in diabetes.
• Receptor-interacting protein kinase 1 (RIPK1) phosphorylation is implicated, but its precise role in diabetic cognitive impairment is unclear.

Purpose of the Study:

• To elucidate the molecular mechanism linking RIPK1, RAGE, and microglial activation in diabetes-associated cognitive deficits.
• To investigate a novel therapeutic strategy targeting the RAGE-RIPK1 interaction.

Main Methods:

• Assessed RIPK1 expression in diabetic patients with cognitive impairment.
• Utilized diabetic mouse models to examine the RIPK1-RAGE interaction in microglia.
• Employed a brain-targeting RIPK1 peptide to block the RAGE-RIPK1 complex.

Main Results:

• RIPK1 expression was elevated in patients and mice with diabetic cognitive impairment.
• The RIPK1 death domain directly binds to the C-terminal of RAGE (ctRAGE), regulating RIPK1 phosphorylation in microglia.
• The RAGE-RIPK1 complex activates inflammatory pathways, exacerbating cognitive deficits.
• The RIPK1 peptide inhibited RIPK1 phosphorylation, reduced neuroinflammation, and improved neuronal function, preventing cognitive decline.

Conclusions:

• A novel mechanism involving RAGE-RIPK1 interaction in microglia contributes to neuroinflammation and cognitive impairment in diabetes.
• Targeting this RAGE-RIPK1 pathway with a brain-penetrant peptide offers a promising therapeutic approach for hyperglycemia-induced cognitive deficits.