Epigenetic Regulation of DAPK1 and Netrin-1 Drives Diabetic Encephalopathy.

Diabetic encephalopathy (DE) is a severe complication of diabetes characterized by cognitive impairment and synaptic dysfunction, while the underlying mechanisms are not clear. Here, a critical role is identified for death-associated protein kinase 1 (DAPK1) in DE pathogenesis using transgenic and streptozotocin-induced diabetic mouse models. Elevated DAPK1 expression in hippocampal excitatory neurons correlates with cognitive deficits, increases neuronal apoptosis, and disrupts synaptic plasticity. Conditional knockout of DAPK1 in CaMKII-positive neurons significantly mitigates these pathological features, improving cognitive performance and synaptic function. Mechanistically, it is demonstrated that reduced hippocampal microRNA (miR)-216a-5p levels in diabetic mice lead to DAPK1 upregulation. Furthermore, DAPK1 suppresses the expression of the neurotrophic factor Netrin-1 (Ntn1) by phosphorylating hepatocyte nuclear factor 1 homeobox A (HNF1A), a key transcription factor. Silencing Ntn1 in wild-type mice induces DE-like symptoms, while intranasal administration of recombinant Ntn1 restores cognitive function and synaptic integrity in diabetic mice. These findings establish an miR-216a-5p/DAPK1/Ntn1 signaling axis as a critical driver of diabetes-induced cognitive dysfunction and suggest Ntn1 as a promising therapeutic target for DE. Here novel insights into the molecular mechanisms are provided underlying DE, and the therapeutic potential of targeting DAPK1 and Ntn1 is highlighted to alleviate diabetes-associated central nervous system complications.