Hypoglycemia aggravates cognitive degeneration by activating endothelial ZBP1-mediated PANoptosis in type 2 diabetic mice.

INTRODUCTION

Recurrent hypoglycemia increases cognitive impairment in diabetic patients. Following cerebral neuron injury, endothelial cells provide morphological, metabolic, and immune support to damaged neurons, but the inflammatory mechanism underlying hippocampal neuron degeneration remains unclear.

METHODS

The Morris water maze test was performed to measure cognitive changes in type 2 diabetic mice. ZBP1 expression was knocked down via small interfering RNA transfection in bEnd.3 brain endothelial cells.

RESULTS

PANoptosis, a defined form of programmed cell death (PCD), was increased by hypoglycemia in the hippocampus of diabetic mice in vivo and by low glucose in bEnd.3 cells in vitro. ZBP1 knockdown reduced low-glucose-induced PANoptosis in high-glucose-cultivated bEnd.3 cells. RNA transcriptomics sequencing revealed that AGE-RAGE signaling was significantly altered after ZBP1 knockdown, which was confirmed by biochemical data.

DISCUSSION: Hypoglycemia impairs cognition in diabetic mice by activating brain endothelial ZBP1-mediated PANoptosis via the AGE-RAGE axis. Targeting ZBP1 may represent a novel therapeutic strategy for diabetes-associated cognitive dysfunction.