Related Experiment Video
Updated: Jul 11, 2025
In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
Published on: January 2, 2015
sTREM2 is associated with attenuated tau aggregate accumulation in the presence of amyloid-β pathology
1School of Medicine, Iran University of Medical Sciences, Tehran, 1449614535, Iran.
Abstract:
Triggering Receptor Expressed on Myeloid Cell 2 (TREM2) plays a crucial role in the transition of microglia from a state of homeostasis to a state associated with the disease. Mutations in TREM2 are strongly linked with a higher risk of developing neurodegenerative diseases, including Alzheimer's disease. There have been contradictory findings regarding the potential detrimental or protective effects of microglial activation and TREM2-related microglial responses in Alzheimer's disease. Although previous studies reported increased CSF soluble TREM2 (sTREM2) in different clinical stages of Alzheimer's disease, the exact association between Alzheimer's disease hallmarks such as amyloid-beta and tau pathology remains unclear. In the present study, I aimed to investigate the association between TREM2-related microglial responses and tau accumulation in the presence and absence of amyloid-beta pathology in order to give a better view of the role of microglial activation in Alzheimer's disease development. Imaging data of 178 non-demented participants including 107 amyloid-beta-negative participants, 71 amyloid-beta-positive were recruited from Alzheimer's disease Neuroimaging Initiative. The CSF sTREM2 was used as an in vivo indicator of microglial responses associated with TREM2. Furthermore, I used longitudinal tau-PET and resting-state functional MRI connectomes in order to investigate the association of TREM2-related microglial activation and tau spreading through functional connections. A higher level of sTREM2 was associated with slower tau aggregate accumulation in non-demented amyloid-beta-positive. Furthermore, measuring the tau spreading through inter-connected regions using functional MRI connectomes confirms that the TREM2-related microglial activity might be a protective factor against tau pathology in brain tissue. These findings demonstrate that in individuals with initial amyloid-beta abnormalities, TREM2-related microglial activation is linked to reduced regional accumulation of tau aggregates and also, spreading across inter-connected brain regions, as evaluated through functional MRI connectomes during the early stages of Alzheimer's disease.
Insights
Triggering Receptor Expressed on Myeloid Cell 2 (TREM2) activity may protect against Alzheimer's disease. Higher TREM2 levels correlate with slower tau buildup and spread in early disease stages, suggesting a protective role for microglia.
Area of Science:
- Neuroscience
- Immunology
- Biochemistry
Background:
- Triggering Receptor Expressed on Myeloid Cell 2 (TREM2) is vital for microglial function and its mutations increase neurodegenerative disease risk.
- The role of TREM2-mediated microglial activation in Alzheimer's disease (AD) pathogenesis remains debated, with conflicting reports on its protective or detrimental effects.
- While elevated CSF soluble TREM2 (sTREM2) is observed in AD, its precise relationship with amyloid-beta and tau pathology is not fully understood.
Purpose of the Study:
- To investigate the association between TREM2-related microglial responses and tau accumulation in individuals with and without amyloid-beta pathology.
- To clarify the role of microglial activation in early Alzheimer's disease development using TREM2 as a biomarker.
- To examine how TREM2-related microglial activity influences tau spreading across functional brain networks.
Main Methods:
- Utilized imaging data from 178 non-demented participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI).
- Measured cerebrospinal fluid (CSF) soluble TREM2 (sTREM2) as an in vivo marker of TREM2-related microglial activity.
- Employed longitudinal tau-PET imaging and resting-state functional MRI (fMRI) connectomes to assess tau accumulation and spreading.
Main Results:
- In non-demented, amyloid-beta-positive individuals, higher CSF sTREM2 levels were associated with slower accumulation of tau aggregates.
- Analysis of tau spreading via fMRI connectomes indicated that TREM2-related microglial activity may confer protection against tau pathology.
- TREM2-related microglial activation was linked to reduced regional tau accumulation and its spread across interconnected brain regions in early AD stages.
Conclusions:
- TREM2-related microglial activation appears to be a protective factor against tau pathology in the early stages of Alzheimer's disease, particularly in the presence of amyloid-beta.
- These findings highlight the potential of targeting TREM2-mediated microglial pathways for therapeutic interventions in Alzheimer's disease.
- Understanding the dynamic role of microglia via TREM2 is crucial for deciphering Alzheimer's disease progression and developing effective treatments.
