Spatial and single-nucleus transcriptomics reveals the molecular pathology of type 2 diabetes-associated cognitive dysfunction.

The mechanisms underlying type 2 diabetes-associated cognitive dysfunction (DACD) remain poorly understood, hindering therapeutic progress. Here, we integrated spatial transcriptomics and single-nucleus RNA sequencing to delineate the spatiotemporal molecular and cellular landscape of DACD in brain tissues from 3- and 6-mo-old mouse models. Our findings revealed region- and cell-type-specific transcriptomic alterations, with excitatory neurons in the hippocampus and isocortex emerging as the most severely affected populations with pronounced synaptic dysfunction. Further analysis of these two regions identified disease-associated transcription factors, such as Rfx3 and Mef2c. In parallel, we uncovered multiple ligand-receptor pairs, including Hsp90b1-Lrp6 and S100a1-Ryr2, whose downstream signaling networks converged on lactate dehydrogenase B (Ldhb) as a shared effector, thereby prompting functional validation. Notably, brain-wide and excitatory neuron-specific Ldhb overexpression alleviated DACD-induced mitochondrial dysfunction, oxidative stress, neuronal apoptosis, and cognitive impairment. Collectively, our study delineates the spatiotemporal transcriptomic landscape of DACD, offers a valuable resource for mechanistic exploration, and highlights Ldhb as a potential therapeutic target in DACD.