Identification of senescent, TREM2-expressing microglia in aging and Alzheimer's disease model mouse brain
Alzheimer’s disease (AD) is an age-related chronic neurodegenerative disorder, whose pathological mechanism involves multiple factors, including brain inflammation. Microglia, particularly those expressing the AD risk gene TREM2, are believed to play a crucial role in the development of AD, but their exact contribution has not been fully elucidated. A recent study found a group of “aged” microglia expressing high levels of TREM2 in aging and disease mouse models associated with amyloid deposition, which exhibited a distinct protein expression profile from the previously discovered TREM2-dependent “disease-associated” microglia (DAM). By depleting these TREM2-expressing “aged” microglia, the researchers improved cognitive function and brain inflammation in the AD mouse model, suggesting that these cells may play a different role from DAM in the pathological mechanism of AD. This study provides a new perspective on our understanding of the dual role of TREM2 in microglial activation and aging.
Authors and Paper Source The research paper was published in Nature Neuroscience by scientists from the Weizmann Institute of Science in Israel, including Noa Rachmian, Michal Schwartz, Valery Krizhanovsky, and others.
Research Workflow The study primarily employed high-throughput mass spectrometry (CyTOF) to analyze microglia in the brains of different aging and AD mouse models, revealing a group of TREM2-high expressing microglia with a unique “aging” signature. The main research process included:
a) Isolating single cells from the brains of aged mice, 5XFAD amyloid deposition model mice, and Tau pathology model mice, and labeling them with metal-ion-conjugated antibodies; b) Analyzing the labeled cells using CyTOF mass spectrometry and identifying cell subsets through clustering algorithms; c) Discovering a group of TREM2-high expressing microglia expressing multiple “aging” markers (such as p16, p21, etc.) in all aging and disease models; d) Observing a significant decrease in the number of this cell group in TREM2-deficient 5XFAD model mice; e) Performing selective depletion of “aged” cells in 5XFAD mice (using the small molecule drug ABT-737), which improved cognitive function and brain inflammation in the model mice.
Research Findings and Significance 1) Discovered a new subset of TREM2-expressing “aged” microglia with a distinct protein expression profile from the previously identified DAM. 2) TREM2 may play dual and opposing roles in microglial activation and aging processes. 3) Depletion of “aged” microglia improved cognitive function and brain inflammation in the AD mouse model, suggesting their involvement in AD pathology. 4) The results reveal the complex role of TREM2 in AD pathogenesis, suggesting caution in considering TREM2 as a therapeutic target for AD. 5) This study provides a new entry point for further exploring the relationship between aging and AD.
Research Innovations 1) First identified a new group of “aged” microglia, enriching our understanding of microglial heterogeneity. 2) The discovery of the new “aged” microglia provides a new perspective on the role of TREM2 in AD pathology. 3) Employed emerging single-cell multi-omics analysis techniques like CyTOF for more accurate and comprehensive phenotypic profiling. 4) Demonstrated that depletion of “aged” microglia can improve AD mouse pathology, providing a potential new therapeutic target for AD.
The activation state and heterogeneity of microglia have been a hot topic in neuroscience research. This study reveals a new role for TREM2 in the aging and activation of microglia, enriching our understanding of microglia and the pathological mechanisms of AD. It provides new insights for the treatment of AD and has significant scientific value and clinical application prospects.