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Peer-reviewedCC BYAdvanced science (Weinheim, Baden-Wurttemberg, Germany)

Single-Cell Dissection of Microglial Dysfunction in Diabetes-Associated Neurodegenerative Vulnerability.

  • Jizhou Zhang1,2
  • Tsz Kwan Yau1,2
  • Joyce Tse1
  • Tsz Ho Li1
  • Dongjie Hu3
  • Yong Juan Zhao3
  • Ting-Fung Chan1,2
  1. 1School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, China.
  2. 2State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong, China.
  3. 3Division of Biomedical Health Sciences, School of Medicine, The Chinese University of Hong Kong, Shenzhen, Shenzhen, Guangdong, China.
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Abstract

The molecular mechanisms linking type 2 diabetes to increased neurodegenerative risk remain poorly defined. Given the critical involvement of microglial dysfunction in neurodegeneration, we constructed a temporal single-cell atlas integrating transcriptomic and epigenomic profiles of microglia from diabetic (db/db) and control (db/m) mice across the lifespan. We delineated a nonlinear, diabetes-specific pathological trajectory characterized by early inflammatory activation, a mid-stage inflection in neurodegeneration-associated signaling and metabolic stress, and late-stage dysfunction. Chromatin accessibility profiling revealed early and persistent epigenomic priming of neurodegeneration-associated pathways, accompanied by stage-specific enhancer rewiring. Pseudotime analysis identified a disease-associated microglial (DAM) state as a candidate transition node, characterized by biased polarization and accelerated maturation under diabetic conditions. Targeted validation using freshly isolated microglia and primary microglial cultures further supported the early expansion of the DAM population, a bias toward homeostatic-to-DAM activation, and Arhgap15-dependent regulation of phagocytic activity. Together, these findings identify microglial states and candidate regulatory pathways that may link diabetes to neurodegenerative vulnerability.

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Cite

BibTeXRIS
BibTeX
@article{zhang2026singlecell,
  title = {{Single-Cell Dissection of Microglial Dysfunction in Diabetes-Associated Neurodegenerative Vulnerability.}},
  author = {Jizhou Zhang and Tsz Kwan Yau and Joyce Tse and Tsz Ho Li and Dongjie Hu and Yong Juan Zhao and Ting-Fung Chan},
  journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
  year = {2026},
  month = oct,
  doi = {10.1002/advs.202600023},
  url = {https://europepmc.org/article/MED/42949627},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Single-Cell Dissection of Microglial Dysfunction in Diabetes-Associated Neurodegenerative Vulnerability.
AU  - Jizhou Zhang
AU  - Tsz Kwan Yau
AU  - Joyce Tse
AU  - Tsz Ho Li
AU  - Dongjie Hu
AU  - Yong Juan Zhao
AU  - Ting-Fung Chan
PY  - 2026
DA  - 2026/10/28
JO  - Advanced science (Weinheim, Baden-Wurttemberg, Germany)
DO  - 10.1002/advs.202600023
UR  - https://europepmc.org/article/MED/42949627
AB  - The molecular mechanisms linking type 2 diabetes to increased neurodegenerative risk remain poorly defined. Given the critical involvement of microglial dysfunction in neurodegeneration, we constructed a temporal single-cell atlas integrating transcriptomic and epigenomic profiles of microglia from diabetic (db/db) and control (db/m) mice across the lifespan. We delineated a nonlinear, diabetes-specific pathological trajectory characterized by early inflammatory activation, a mid-stage inflection in neurodegeneration-associated signaling and metabolic stress, and late-stage dysfunction. Chromatin accessibility profiling revealed early and persistent epigenomic priming of neurodegeneration-associated pathways, accompanied by stage-specific enhancer rewiring. Pseudotime analysis identified a disease-associated microglial (DAM) state as a candidate transition node, characterized by biased polarization and accelerated maturation under diabetic conditions. Targeted validation using freshly isolated microglia and primary microglial cultures further supported the early expansion of the DAM population, a bias toward homeostatic-to-DAM activation, and Arhgap15-dependent regulation of phagocytic activity. Together, these findings identify microglial states and candidate regulatory pathways that may link diabetes to neurodegenerative vulnerability.
SN  - 2198-3844
ER  -