Authors
Wei Wu, Yumeng Yang, Xixi Zhang, Baojian Liao, Siyu Kong, Bingbing Xie, Yanping Lu, Mingyue Jiang, Xiu Liang, Lei Zhang, Meiyi Zhou, Xiaojing Zhang, Ningyi Shao, Gholson J Lyon, Yaqing Shu, Shengbao Suo, Ning Ma
Published in
Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 41. Pages e2529793123. Oct 13, 2026. Epub Oct 06, 2026.
Abstract
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.
PMID:
42837462
Bibliographic data and abstract were imported from PubMed on 07 Oct 2026.
Read full publication at:
Please sign in
to see all details.
Advertisement
Stats
- Recommendations n/a n/a positive of 0 vote(s)
- Views 26
- Comments 0