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

Microglial activation can cause neuroinflammation and the consequent neurological impairments play prominent roles in diabetes-associated cognitive deficits. Receptor-interacting protein kinase 1 (RIPK1) phosphorylation is involved in this deleterious microglial activation, but the exact molecular mechanisms are not clear. Here, RIPK1 expression was increased in diabetic patients with cognitive impairment. Furthermore, in diabetic mice, RIPK1 death domain directly binds to C-terminal of the receptor for advanced glycation end products (ctRAGE) could regulate RIPK1 phosphorylation in microglia. This RAGE-RIPK1 complex activates inflammatory signaling, resulting in cascades that ultimately promote cognitive impairment in diabetic mice. An engineered brain-targeting RIPK1 peptide blocked binding of RIPK1 to RAGE, which inhibited RIPK1 phosphorylation, decreased neuroinflammation, improved neuronal morphology and function, and prevented diabetes-associated cognitive deficits in mice. This study uncovers a previously unknown mechanism of neuroinflammation and suggests a novel therapeutic avenue for treating cognitive deficits induced by hyperglycemia.