Zhimu-Huangbo herb pair ameliorates diabetic cognitive impairment by modulating the CCL3-CCR5 axis-dependent...

Diabetes-induced cognitive impairment (DCI), with its incompletely elucidated pathological mechanisms, currently lacks FDA-approved therapeutic agents in clinical practice. The traditional Chinese medicine pair Zhimu-Huangbo (ZMHB) exhibits neuroprotective and immunomodulatory effects, but its role in DCI via neuroimmune crosstalk is unclear.

This study aims to elucidate the pathogenesis of DCI from the perspective of neuroimmune interactions and explore the therapeutic effect of ZMHB, to provide new strategies for the prevention and treatment of DCI.

A type 2 diabetic mouse model was established by high-fat diet combined with streptozotocin (STZ) injection and treated with ZMHB for 8 weeks. Cognitive function was assessed by Morris water maze, brain transcriptional signatures were profiled by single-cell RNA sequencing (scRNA-Seq), and key findings were validated by immunofluorescence, flow cytometry and splenocyte migration assays. In vitro studies further delineated the active components and molecular mechanisms.

ZMHB significantly ameliorated cognitive function and prevented neuronal apoptosis in T2DM mice. scRNA-Seq revealed that ZMHB profoundly reversed T cell receptor and chemokine signaling pathways, specifically, downregulating neuronal CCL3 expression, which disrupted neuron-CD8⁺ T cell crosstalk and reduced brain infiltration of CCR5⁺ CD8⁺ T cells. CCR5 antagonism similarly prevented CCR5⁺CD8⁺T cell brain infiltration and reversed cognitive impairment. Berberine was identified as the principal active component of ZMHB that suppresses neuronal CCL3 expression by inhibiting the non-canonical NF-κB2 pathway.

This study reveals a novel neuroimmune mechanism underlying DCI and demonstrates that ZMHB ameliorates DCI by targeting the CCL3-CCR5 axis-dependent interaction between neurons and CD8⁺ T cells.