An interfering peptide attenuates diabetic encephalopathy by blocking the interaction between CD44 and STAT3

Diabetic encephalopathy (DE) is one of the main neurological complications of diabetes, but its pathogenesis remains unclear. Here, we show that elevated CD44 in diabetes patients is associated with impaired cognition, and it contributes to diabetic cognitive deficits by interacting with STAT3. We identified a region of the CD44 C-terminal (residues 722-729) that binds directly to the SH2 domain of STAT3, promoting STAT3 phosphorylation and nucleus translocation. To explore the therapeutic potential of this mechanism in DE, we designed an interfering peptide that blocks formation of the CD44-STAT3 complex. Administration of this CD44-peptide prevented STAT3 phosphorylation and activation of the downstream apoptosis-related signaling pathway both in vitro and in vivo, and ameliorated hippocampal synaptic deficits and cognitive impairments in db/db mice. In conclusion, we demonstrated that the formation of the CD44-STAT3 complex under hyperglycemia conditions is a crucial trigger for neuronal apoptosis; targeting this complex may provide a novel therapeutic avenue for DE.