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Background <p>Cognitive dysfunction associated with type 1 diabetes (T1D) is closely linked to the accumulation of amyloid-beta (Aβ) oligomers. However, the role of microglia and their underlying molecular mechanisms in this process remain unclear. Triggering receptor expressed on myeloid cells 2 (TREM2), a microglial receptor critical for clearing neurotoxic Aβ and maintaining metabolic homeostasis, is dysfunctional in Alzheimer’s disease. Here, we investigated TREM2-mediated microglial dysfunction in diabetic neurodegeneration.</p> Purpose <p>To investigate the role of TREM2-mediated microglial dysfunction in Aβ clearance and cognitive impairment in T1D.</p> Basic procedures <p>A total of 204 male C57BL/6J mice, aged 6–8 weeks, were used in this study. We performed single-nucleus RNA sequencing (snRNA-seq) on 59,356 cells from the prefrontal cortex and hippocampus. Aβ pathology was evaluated by western blot, immunofluorescence and ELISA. TREM2 knockout mice and the murine microglial cell line BV2 were used to study the role of TREM2 in cognitive function and Aβ clearance.</p> Main findings <p>T1D mice exhibited progressive memory deficits and prefrontal Aβ oligomer accumulation (36–50&#xa0;kDa), with region-specific microglial activation. SnRNA-seq identified ten microglial subpopulations, with Trem2-enriched clusters (M1/M2/M3/M5) showing impaired phagocytosis and metabolic dysregulation. TREM2 knockout exacerbated cognitive deficits and Aβ accumulation in T1D mice. Mechanistically, TREM2 regulated microglial migration, phagocytosis of Aβ oligomers, and mitochondrial integrity under high-glucose conditions, potentially via the mTOR signaling pathway.</p> Principle conclusions <p>These findings establish TREM2 as a critical regulator of microglial Aβ clearance in T1D, operating mitochondrial and phagocytic programs via mTOR and highlighting its therapeutic potential for diabetic neurodegeneration.</p>

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Cognitive dysfunction in type 1 diabetes: role of TREM2 in microglial activation and Aβ pathology

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月2日

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  • Yue Wang,
  • Ruyue Wang,
  • Yimeng Liu,
  • Zhaohui Wang,
  • Hongyan Ding,
  • Xinyi Wei,
  • Aikeda Aihemaitijiang,
  • Minghan Sun,
  • Li Zhao

摘要

Background

Cognitive dysfunction associated with type 1 diabetes (T1D) is closely linked to the accumulation of amyloid-beta (Aβ) oligomers. However, the role of microglia and their underlying molecular mechanisms in this process remain unclear. Triggering receptor expressed on myeloid cells 2 (TREM2), a microglial receptor critical for clearing neurotoxic Aβ and maintaining metabolic homeostasis, is dysfunctional in Alzheimer’s disease. Here, we investigated TREM2-mediated microglial dysfunction in diabetic neurodegeneration.

Purpose

To investigate the role of TREM2-mediated microglial dysfunction in Aβ clearance and cognitive impairment in T1D.

Basic procedures

A total of 204 male C57BL/6J mice, aged 6–8 weeks, were used in this study. We performed single-nucleus RNA sequencing (snRNA-seq) on 59,356 cells from the prefrontal cortex and hippocampus. Aβ pathology was evaluated by western blot, immunofluorescence and ELISA. TREM2 knockout mice and the murine microglial cell line BV2 were used to study the role of TREM2 in cognitive function and Aβ clearance.

Main findings

T1D mice exhibited progressive memory deficits and prefrontal Aβ oligomer accumulation (36–50 kDa), with region-specific microglial activation. SnRNA-seq identified ten microglial subpopulations, with Trem2-enriched clusters (M1/M2/M3/M5) showing impaired phagocytosis and metabolic dysregulation. TREM2 knockout exacerbated cognitive deficits and Aβ accumulation in T1D mice. Mechanistically, TREM2 regulated microglial migration, phagocytosis of Aβ oligomers, and mitochondrial integrity under high-glucose conditions, potentially via the mTOR signaling pathway.

Principle conclusions

These findings establish TREM2 as a critical regulator of microglial Aβ clearance in T1D, operating mitochondrial and phagocytic programs via mTOR and highlighting its therapeutic potential for diabetic neurodegeneration.