Related Experiment Video

Updated: May 31, 2026

Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
09:12

Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates

Published on: January 30, 2014

TGM2 drives microglial senescence by inhibiting autophagy via the PI3K/AKT/mTORC1 pathway

Zhiqiang Li1, Yuxiang Tang2, Dongyuan Zhang3

  • 1CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, 200031, China; Zhejiang Key Laboratory of Multiomics and Molecular Enzymology, Yangtze Delta Region Institute of Tsinghua University, Jiaxing City, Zhejiang Province, 314006, China.

Free Radical Biology & Medicine
|May 29, 2026
PubMed

Insights

Transglutaminase 2 (TGM2) links microglial senescence to impaired autophagy, driving neurodegeneration. Inhibiting TGM2 restores autophagy and reverses cognitive deficits in aged mice, offering a potential therapeutic target.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Aging Research

Background:

  • Microglial senescence contributes to age-related neurodegeneration.
  • Senescence impairs autophagy and increases neuroinflammation.
  • Molecular links between microglial senescence and autophagy dysfunction are poorly understood.

Purpose of the Study:

  • To identify molecular mechanisms connecting microglial senescence and autophagy dysfunction.
  • To investigate the role of transglutaminase 2 (TGM2) in this process.
  • To evaluate TGM2 inhibition as a therapeutic strategy for age-related neurodegenerative disorders.

Main Methods:

  • Identified TGM2 upregulation in senescent microglia.
  • Characterized a novel signaling complex involving TGM2, 14-3-3γ, and PI3K.
  • Assessed the impact of TGM2 inhibition with cystamine dihydrochloride (CD) on autophagy, SASP, ROS, and cognitive/motor functions in aged mice.

Main Results:

  • TGM2 is selectively upregulated in senescent microglia.
  • TGM2 forms a complex with 14-3-3γ and PI3K, sustaining AKT phosphorylation and inhibiting mTORC1-mediated autophagy.
  • Pharmacological inhibition of TGM2 restored autophagy, reduced SASP and ROS, and reversed cognitive and motor deficits in aged mice.

Conclusions:

  • TGM2 is a critical regulator linking microglial senescence to autophagy dysfunction.
  • Targeting TGM2 signaling offers a potential therapeutic avenue for age-related neurodegenerative diseases.
  • Restoring microglial autophagy via TGM2 inhibition may ameliorate neuroinflammation and cognitive decline.
Keywords:
AutophagyMicroglial senescencePI3K/AKT/mTORC1 pathwayTransglutaminase 2

More Related Videos

Drug-Induced Senescence in Liver Cells Promotes M2 Macrophage Polarization: Implications for Tyrosine Kinase Inhibitor-Associated Hepatotoxicity09:32

Drug-Induced Senescence in Liver Cells Promotes M2 Macrophage Polarization: Implications for Tyrosine Kinase Inhibitor-Associated Hepatotoxicity

Published on: October 17, 2025

Related Concept Videos

mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...